DE2031227A1 - New substituted Sahcylsauren and process for their production - Google Patents

Description

New Substituted Salicylic Acids and Processes for their production

The development of anti-inflammatory compounds has Over the past two decades a great many new remedies have been spawned, most of which are made up of steroids of the series of 11-oxygen! erten pregnans. These connections Although they are very effective, «have the disadvantage that they cause many side effects. on In the market there is a need for equally effective compounds with a much simpler structure, the lesser one Show side effect.

The present invention relates generally to new, Substituted salicylic acid compounds and processes for making the same · The present invention also relates to pharmaceutical agents containing said salicylic acid compounds as an active ingredient, as well as methods of treating inflammation by administering these particular agents to patients. Some of the-

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These compounds show an additional useful degree from antipyretic, analgesic, diuretic, antifibrinolytic and hypo-glycemic effectiveness.

The present invention relates to new, substituted salicylic acids and processes for making the same, in particular substituted salicylic acids, esters, amides, anhydrides and non-toxic, pharmaceutically acceptable salts thereof. In particular, the present invention relates to compounds the following general formula s

(D

Herein mean:

R Bydroxy, amino, lower alkoxy (such as methoxy, ethoxy, Butoxy, pentoxy etc), lower alkylamino (methylamino, Propylamino, pentalamino etc.), di (lower alkyl) amino (Dimethyl amino, dibutylamino, propylpentylamino etc.), Di-lower alkylamino-lower-alkylamino, di-lower-alkylamino-lower alcohol Hydroxynloweralko3 {y (3-5ydroxypropoxy, 2-Hydroxypropoxy, -4-Bydrosybutoxy etc), Polyhydroxynlowalkoxy (2,3-Dihydroxypropoxy, 2,3,4,5 »6-Pentahydro ^ hesyloxy etc.), Medrigalkoxyniedrigalkosy (Ethoxyethoxy etc.), phenyl lower alkoacy (benzyloxy, Phenylethoxy etc)., Phenoxy, substituted phenoxy (such as lower alkoxyphenoxy, halophenoxy, di-lower alkylaminophenoxy, Lower alkanoylaminophenoxy, carboxyphenoxy and carbo-lower alkoxyphenoxy), phenylamino, Hydrazino, morpholino, N-piperidino, pyrrolidino or

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Hydroxy lower alkyl amino ν

Hydrogen, acyl (preferably lower acyl, such as formyl, Acetyl, propionyl, butyryl etc.), alkyl (preferably lower alkyl, such as methyl, ethyl, propyl, isopropyl, Butyl, pentyl etc.), or alkoxycarbonyl (preferably Lower alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, Hexoxycarbonyl etc.) 4

R * hydrogen, halogen (such as chlorine, bromine, fluorine or iodine, preferably fluorine or chlorine), haloalkyl (preferably halide acidic alkyl, such as trifluoromethyl etc.), alkyl (preferably lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl etc.), cycloalkyl, etc.

(Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and Cycloheptyl) or alkoxy (preferably lower alkoxy, such as methoxy, ithoxy, isopropoxy or butoxy) 4

X hydrogen, alkyl »(preferably lower alkyl, such as Methyl, ethyl, propyl, isopropyl, butyl, pentyl etc.), Hydroxy, alkoxy (preferably lower alkoxyV such as methoxy, Acetoxy, isopropoxy or butoxy), acyloxy (such as benzoyloxyacetoxy or propionoxy), halogen (such as chlorine, bromine, fluorine or iodine, preferably fluorine or chlorine), haloalkyl (preferably halo-lower alkyl, such as trifluoromethyl etc.), nitro, amino, alkylamino (preferably Lower alkylamino such as methylamino, propylamino ^ pentylamino etc.), di-lower alkylamino (dimethylamino, di- I butylamino, propylpentylamino, etc.), acylamino (preferably Lower acylamino, such as formylamino, acetylamino, Propionylamino, butyrylamino etc.), mercapto, alkyl mercapto (preferably lower alkyl mercapto, such as Methyl mercapto, ethyl mercapto etc.), alkylsulfinyl (preferably lower alkylsulfinyl, such as methylsulfinyl, Ethylsulfinyl, butylsulfinyl etc.), alkylsulfonyl (preferably lower alkylsulfonyl, such as methylsulfonyl,

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ethylsulfonyl, butylsulfonyl, etc.), sulfonamido, sulfonylamido, alkylaminoalkyl (preferably lower alkylamino-lower alkyl, such as methylaminomethyl, ethylaminomethyl, etc.), dialkylaminoalkyl (preferably di-lower alkylamino-lower alkyl, such as dimethylaminomethyl, • diethylaminoethyl, such as dimethylaminomethyl, hydroxy-alkyl, such as dimethylaminomethyl, hydroxy-alkyl, such as hydroxy, hydroxy-alkyl, such as hydroxy, hydroxy-alkyl, such as hydroxy-hydroxy-alkyl, such as hydroxy, hydroxy-alkyl, such as hydroxy, preferably hydroxy-ethyl (etc, preferably hydroxy-ethyl-lower-alkyl, etc., preferably hydroxy-ethyl-lower-alkyl (etc), preferably lower-alkylamino-lower-alkyl (etc), preferably hydroxy-ethyl-lower-alkyl, preferably lower-alkylamino-lower-alkyl, preferably lower alkylamino-lower-alkyl, preferably lower-alkylamino-lower-alkyl, etc. etc), alkoxyalkyl (preferably lower alkoxy-lower alkyl, such as methyl, metho ^ äthyl, A'thoxyäthyl, Athosq ^ propyl etCo), mercaptoalkyl (preferably mercapto-lower alkyl, such as mercaptomethyl, mercaptoethyl etc.), Alkyliäercaptoalkyl (preferably medrigomethylmercaptoethylmercaptylmercaptyl mercaptoethylmercaptoalkyl, such as mercaptomethyl, mercaptoethyl, etc.) Ät3aylmercaptopropyl etCO), cyano, carboxy, carbalkoxy, (Cerbomethoxy, CarbätlLOxy etc) "carbamoyl, aryl (such as phenyl, halophenyl _t tolyl, salicyl), aralkyl such as benzyl, phenylethyl etc, aryloxy or arylalkoxy;
Y !! ethyleneimino (-CH ₂ MH-), iminomethylene (-HHCHg-), methylidenenitrilo (-CH ^ N-), kitrilomethylidene, (-K ^ CH-),

Carbonylimino (-C-NH), or iminocarbonyl (-KH-C-);

with the proviso that the OR ^ group is always ortho to the

C - R group stands.

Representative compounds according to the invention are following:

4- (p, ο or m-pluorbenzylideneamino) salicylic acid; 5- (p »ο or m-5 ¹ luorbenzylidenamino) salicylic acid; 4- (p, ο or m-fluorobenzylamino) salicylic acid; 5- (p, o or m-I'luorobenzylamino) salicylic acid; ^ - (p> ο or m-fluorobenzamido) salicylic acid;

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5-CPj ο or m-fluorobenzamido) salicylic acid; 4 ~ (p, o or m-fluoroanilineQmethyl) salicylic acid; 5- (p> ο or m-fluoroanilinomethyl) salicylic acid; 4- (ρ, ο or m-fluorophenyliminoraethyl) -s.alicylic acid; 5- (ρ ν ο or m-fluorophenyliminomethyl ^ salicylic acid; and the corresponding salts, esters, anhydrides and amides.

The present invention also relates to a method for Treating inflammation in patients using a compound of formula I, especially a particular one preferred compound as the active ingredient.

The compounds according to the invention can be used for treatment of inflammation by reducing inflammation and relieving pain in such conditions as rheumatoid arthritis Arthritis, osteoarthritis .., gout, infectious arthritis and rheumatic fever. Also wise the compounds according to the invention have better activity at the same dosage levels than compounds of a similar nature belonging to the known prior art and show a lower incidence of side effects «

The compounds of formula I also have antipyretic, analgesic, diuretic, antifibrinolytic and hypoglycemic Effectiveness on and become, if this effectiveness is to be exploited, in the same way and in the same way Dosage ranges administered and used as in their use on · 'treatment of inflammation, such as Will be discussed further below ".

The treatment of inflammation according to the procedure de> r. The present invention is carried out by administering an agent to the patient orally, rectally or parenterally, since i a compound of the formula I, in particular the particularly be

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the aforesaid compounds in a non-toxic, pharmaceutical form contains acceptable carrier «.

The non-toxic, pharmaceutically acceptable carrier can also. be a solid or a liquid, for example «Exemplary for solid carriers are lactose, corn starch, gelatine, Talc, Sterotix, stearic acid, magnesium stearate, terra alba, Sucrose, agar, pectin, Cab-o-sil and acacia ("acacia") · Examples of liquid carriers are peanut oil, olive oil, Sesame oil and water. Similarly, the carrier or diluent can be a delay material such as Glyceryl monostearate or glyceryl distearate, alone or with a wax included.

Various pharmaceutical forms of the therapeutically useful agents can be used · If, for example A solid, support is used, the funds can take the shape of tablets, capsules, powders, lozenges or lozenges, which are manufactured according to standard pharmaceutical methods assume «When using a liquid carrier the preparation can be in the form of a soft gelatin capsule, a syrup or a liquid suspension. Suppositories for rectal administration and gels, lotions, etc. for topical use can be prepared in a conventional manner will.

The active compounds of the formula I and those according to the invention Agents are administered in an amount sufficient to treat inflammation, i. E. about inflammation to diminish. Advantageously, the agent contains the active ingredient, namely the compounds of formula I, in an amount of about 1 mg to 100 mg ge kg of body weight per day (50 mg to 7 g per patient per day), preferably from

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about 2'mg "to 50 mg / kg body weight per day (100 mg" to

3 g per patient per day)

The treatment method according to the invention comprises the administration to a patient (animal or human) of a compound of the formula I, in particular a particularly preferred compound in admixture with one of the non-toxic, pharmaceutical carriers exemplified above. The compounds of formula I and in particular the most preferred compounds are in an amount of 1 mg to 100 mg / kg body weight per day, preferably from about 2 mg to about {50 mg / kg of body weight per day, and especially from

4 mg to 20 mg / kg body weight administered per day. The fastest and most effective anti-inflammatory effect will be at oral administration at a daily dosage of about 4- to 20 mg / kg / day received. It is understood, however, that although preferred dosage ranges are given, the Dose level for any particular patient will depend on the effectiveness of the particular compound being used. Also, by those skilled in the field of therapeutic use of drugs, in particular by those skilled in the art of Formula I, many other factors which modify the effects of the medicaments, e.g. B. Age, body weight, Gender, diet, duration of administration, route of administration, "excretion rate, drug combination, reaction sensitivities and severity of the specific disease,

to be billed. .

The benzalaminosalicylic acids according to the invention can by Implementation of an aminosalicylic acid with a substituted benzaldehyde.

The benzalaminosalicylic acid compounds can then be added to the

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Substituted benzylaminosalicylic acid compounds according to the invention »The benzylaminosalicylic acid compounds can also be reduced by way of direct benzylation made from sodium (or potassium) salicylate in ethanol containing anhydrous potassium carbonate

The anilinomethylsalicylic acid compounds according to the invention can by Ünrsetaen a halomethyl, salicylic acid with a substituted aniline can also be prepared by reacting a methyl halogen-substituted Methyl salicylate with a substituted aniline and through Hydrolyzing the resulting methyl anilinomethyl salicylate getting produced"

The benzamidosalicylic acid compounds according to the invention can be prepared by reducing a 4- (or 5-) nitromethyl anisole to an aminomethyl anisole, reacting the aminomethyl anisole with a substituted benzoyl halide to form a benzamido anisole, demethylating said benzamido anisole to a benzamidophenol and carboxylating said benzamidophenol _s or by way of the direct benzoylation of an aminosalicylic acid.

The arfindungsgemässen Ehenyliminomethylsalicylsäure compounds can be prepared by reacting 4-- (or 5-) ~ ormyl ^F-salicylic acid with a substituted aniline can be prepared.

Those compounds according to the invention in which E signifies such a group that the end compounds are esters (i.e. ho B »alkoxy), are prepared by any esterification procedure using an esterification agent which contains the suitable R group, prepared »For example, the acid compounds according to the invention can be

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suitable lower alkanol (preferably methanol) at elevated levels ! Temperatures in the presence of a strong acid such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like, implemented with separation of the desired 'ester will.

Those compounds according to the invention in which R is a such group means that the end compound is an amide (i.e., R is amino), any suitable Amidation reaction can be produced. For example the acid compound (preferably the methyl or ethyl ester) with ammonia, ammonium hydroxide or a Amide compound can be reacted at any suitable temperature (room temperature to reflux temperature). Venn the amino group is desired, the reaction is preferably carried out with ammonia in a bomb at temperatures of about 100 ° C to form the desired R- (amino) compound · If an amide is desired that differs from a Amino acid derived, the following reaction sequence is preferably used: The benzoic acid end compound is with Isobutyl chlorocarbonate to form the mixed anhydride, implemented. This compound is in turn reacted with the desired amino acid ester and subsequently hydrolyzed to the desired amide.

The end compound in which R 2 is lower alkyl (preferably methyl) can be according to any suitable Alkylation reaction can be produced. For example k8nxieri the corresponding hydroxybenzoic acids the corresponding !! star or the corresponding amide (preferably the ester) with a di (lower alkyl) sulfate (preferably dimethyl sulfate) in the presence of a base (such as alkali carbonate) at any suitable temperature (room temperature to reflux! β temperature; but preferably at or near

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the reflux temperature) and the reaction mixture subsequently acidified to form the desired Rg compound be e.g. B · with hydrochloric acid, sulfuric acid and the same.

The salts of the finally obtained acid compounds according to the present invention can be prepared by any of the known metathesis procedures. For example, the acid compound can be reacted with an inorganic base such as sodium hydroxide and the like
the working methods belonging to the known state of '! Cechnik are produced »

The following examples are zer further illustrate the invention%

example 1

5- (p- Fluorobenzobylamino) -s alicy lsanre

To 0.01 m methyl 5-aminosalicylate in fyridine at 10 ° C wer-r while stirring in the course of 10 minutes 0.01 m p-fluorobenzoyl chloride The resulting mixture is allowed to warm to tree temperature, stir it overnight, add excess, Add dilute hydrochloric acid, stir and collect the methyl 5- (p-fluorobenzoylamide salicylate and hydrolyze it under standard conditions, one obtains *> - (p-fluorobenzoylamino) salicylic acid (M.p. 280 to 281 ° C)

If other substituted benzoyl chlorides, e.g. B. o-fluorine, m-fluorine, o-, m- and p-chlorine, o, m- and p-methoxy-, o-, m- and p-trifluoromethyl, o-, m- and p-nitro, o-, m- and p-dimethylainino (or hydrochloride), o-, m- and p-acetamido,

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ο-, m- and p-methylmercapto-, ο-, m- and p-carbomethoxy-, ■ o-, m- and p-phenyl-, o-, m- and p-benzyl-, o-, m- and p-phenoxy-, o-, m- and p-benzyloxy- or o-, m- and p-acetylbenzoyl chloride, used, the corresponding substituted 5-benzamidosalicylate is obtained.

. j

When considering the 3-chloro, 3-methoxy, 3-methyl and 4-fluoro analogs of the 5-AmInOS alicylate in the above example used instead of methyl 5-aminosalicylate, one obtains the corresponding substituted salicylates. Using methyl-4-amino analogs in the above .working

used, one obtains the corresponding, substituted {

Salicylates.

The benzoylations described above can be followed by others Methods known to those skilled in the art, such as by adding the benzoyl halide to an aqueous solution blanketed with nitrogen of a metal salt, such as a sodium or potassium salt, of salicylic acid with the addition of a base, to the; To keep the pH of the reaction mixture at 8, carried out only those benzoyl halides are used with this procedure, which have groups, which are compatible with aqueous hydroxide.

B is ρ 1 e 1 2 ' . '

5- (ji- fluorobenzylideneamino) -s alicylic acid

A mixture of 0.005 m and 0.005 m 5-aminosalicylic acid p-fluorobenzaldehyde in 150 ml of ethanol, is protected from moisture and heated for 5 hours, concentrated and cooled and the 5- (pi ^l l ".orbenzylidenamino) salicylic acid is collected.

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A trace of p-ioluene sulfonic acid can be found in the one described above Reaction can be used as a catalyst.

If one uses o- and m-fluorobenzaldehyde, o ~, m- and p-chlorobenzaldehyde, o-, m- and p-methylbenzaldehyde, p-dimethylaminobenzaldehyde, o-, m- and p-trifluoromethylbenzaldehyde, p-acetamidobesaldehyde, o-, m ~ and p-methylthiobenaaldehyde, p-CyanobenBaldehyde, m- and p-Benzyloabaldehyde, Biphenylcarboxaldehyd, Benzylbenzaldehyde, p-Hienoxybenzaldehyd, p ~ Acetylbenaaldehyde, p-methylsulfonyibenzaldehyde, dichlorobenzaldehyde, Oirichlorobenzaldehyde, 2,3, ^, 5-ipetramethylbenzaldehyde or p-carbomethoicybenzaldehyde instead of p-fluorobenzaldehyde When used in the procedure described above, the corresponding substituted benzalaminosalieyl acids are obtained.

If you have 3-chloro, 3-methoxy ~, 3-methyl or 4 ~ fluoro analogues of 5-aminosalicylic acid instead of 5-amino-balicylic acid Used in the example described above, the corresponding substituted salicylic acids are obtained.

If you have 4-aminosalicylic acid and its analogues instead of 5-aminosalicylic acid in the procedure described above used, num receives the corresponding, substituted ones Salicylic acids.

Beis piel?

5- Op-Pluorbenzylamino) ~ salicylic acid

A mixture of 0.01 m 5- (p-fluorobenzylideneamino ^ salicylic acid, 50 ml ethanol and 0.5 g palladium (5%) - on charcoal is added in a hydrogen atmosphere (2.81 kg / cm \ 40 psi) at Room temperature implemented until 0.01 m water

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The mixture is filtered, the cake is washed well with ethanol, and the filtrates are combined and concentrated in vacuo. 5- (p- ■■ Fluorobenzylamino ^ salicylic acid .

The above-described reduction can be performed using Metal hydrides can be achieved as reducing agents.

The above product can also be purchased via the direct p-fluorobenzylation of sodium (or potassium) 5-aminosalicylate in ethanol, the anhydrous potassium carbonate contains, are obtained. ,

If one uses the substituted benzylideneamino compounds of the Example 2, which is compatible with the heduction conditions are treated with hydrogen as indicated above, the corresponding substituted 5-benzylamine-psalicylic acids are obtained.

B e i s ρ i e 1 4

5 ~ (-p ~ fluoranilinomethyl) -salicylaic acid

A mixture of 0.01 M methyl J-chloromethyl salicylate and λ 0.01 M p-fluoraniline in 25 ml of methanol containing anhydrous potassium carbonate is heated for 8 hours, cooled and filtered. The cake is washed well with fresh methanol. The combined filtrates are concentrated in vacuo. The residue is taken up in chloroform, dried and filtered, and the chloroform is removed in vacuo. The residue is chromatographed on a silica gel column using an ether / petroleum ether system ( ^v / v 10-100% ether) as the eluent. It yields methyl ~ 5 ~ (p-fluoroanilinomethyl) salicylate. By hydrolysis

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of the ester is obtained

If you have ο- and m-fluoroaniline, the toluidines, the anisidines, ο-, m- and p-chloroaniline, the 3h? Ifluoromethylaniline, o-, m- and p-bitroaniline, o-, m- and p-methylthioaniline , llethyl paminobenzoate, the bipehnylamine _? p-benzylaniline, 4-aminophenyl ether and 4-benzyloxyaniliB. used instead of p-fluoroaniline in the reaction described above, the corresponding β-C is obtained

Beis piel. 5A

A shaker lined with stainless steel. 0.1 mc6-nitro ~ m-anisic acid is charged under a nitrogen atmosphere, the system is cooled in dry ice, 0.5 m sulfur tetrafluoride is condensed into the tube, and the mixture is then heated to 120 ° C for 8 hours. After cooling, the tube is ventilated, the material is taken up in chloroform, the chloroform mixture is washed with dilute bicarbonate solution, the chloroform is dried, filtered and concentrated in vacuo, and the residue is placed on a silica gel column using an Ither petroleum ether system ( ^v / v 0 - 80% Ither) as the eluent. J-trifluoromethyl - ^ - nitroanisole is obtained.

Example 5B

4-Cp "" gluorbenzamido) 3-trifluoromethyl anisole

One. Mixture of 0.1 m ^ -nitro-J-trifluoromethylanisole and 2 g palladium (5%) - on charcoal catalyst in 500 ml Ethanol is mixed with hydrogen (2.81 kg / cm) at room temperature implemented. When the hydrogen uptake has stopped,

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the mixture is filtered and the ethanol is removed in vacuo. 300 ml of anhydrous iyridine are added. If the resulting mixture with p-pluorbenzoyl chloride vie in Treated Example 1, 4- (p-fluorobenzamido) -3-trifluoromethylanisole is obtained.

If the substituted benzoyl halides of Example Λ are used instead of p-fluorobenzoyl chloride in Example 6 above, the corresponding substituted benaamidoanisole is obtained.

If the above-obtained free amino compound is substituted with Benzyl halides are benzylated as in Example 3 or pyridine is used as the solvent base the correspondingly substituted benzylaminoanisole.

Example 50

■ p-. (4 ~ fluorobenzamido) -m-trifluoromethylphenol

A mixture of 5 g of p- (4-fluorobenzamido) -m-trifluoromethyl anisole and 25 g of pyridine hydrochloride is under one

dry nitrogen atmosphere in an oil bath heated to 230 ° C, left in it for 10 minutes and. cooled. The mixture is extracted with chloroform. The chloroform extracts are washed with water, dried and concentrated in vacuo, and the residue is chromatographed on a silica gel column using a ethanol-methylene chloride ( ^v / v 0-50 % methanol) system as the eluent. P- (4-Pluorbenzamido) -m-trifluoromethylphenol is obtained.

If one considers the other substituted benzamido and substituted

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performed benzylaminoanisoles of Example 5B and 4-amino-3-trifluoromethylanisole from Example 5B with pyridine hydrochloride, as described above, reacted, one obtains the corresponding phenols. Other standard ways of working for demethylation can also be used.

example

An intimately ground mixture of 5 S P ~ (4-fluorobenzamido) »3 ~ trifluoromethylphenol and 15 g of anhydrous potassium carbonate is heated to 200 ° C. for 8 hours in a carbon dioxide atmosphere (8 * 1-, 4 to 98.4 kg / cm) The mixture is cooled, added to 300 ml of water, stirred, filtered, and the piltrate is neutralized with dilute hydrochloric acid. This gives 5- ^(p-F luorbenzamido) -4-trifluorme thyls alicyls CDCR e "

If the phenols of example 5C are mixed with carbon dioxide, reacted as described above, the corresponding substituted salicylic acids are obtained.

At JB ν i e 1 6

If you have 5-amino-4-trifluoromethylsalicylic acid with p-pluobenzaldehyde reacted as in Example 2, 5- (p ~ i'luorobenzylideneamino) -4-trifluorinethyl ~ salicylic acid is obtained.

If you use the benzaldehydes of Example 2 instead of p-pluobenzaldehyde Used in the above case, the correspondingly substituted 5-benzylidene amino salicylic acid is obtained.

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Example 7

Methyl 5- (T) -hydroxybenaylamino) aalicylate

If you methyl ^ -Cp-methoxybenzylamino ^ salicylate with fyridine hydrochloride as implemented in Example 50, one obtains Methyl 5- (p-hydroxybenzylamino) salicylate.

B e is ν ie 3. θ

Methyl 5- ('P * -mercaptobengamido) ~ 3alicylate

- _i

If you have methyl - ^ - Cp-methyltMobenzamido ^ salicylate with pyridine hydrochloride reacted as in Example 50, methyl 5- (p-mercaptobenzamido) salicylate is obtained.

B ei s. Υ ie 1 9 methyl- 5- (τ> - am in above ami dos alicylate)

If you have methyl 5 ~ (p-nitrobenzamido) salicylate in methanol with hydrogen under the reducing conditions of the example 5B converts, methyl 5- (p-aminobenzamidosalicylate is obtained.

If you use the nitro compounds of Examples 1 and 3 at | used the procedure given above, one obtains the corresponding amino-substituted compounds.

B. e. 1 s ρ ie 1 10 '

^ - (p-> Hethylsulfinylbenzamido) ~ salicylic acid

0.01 m of 5- {pI ⁱ ethylthiobenzamido) salicylic acid in methanol-acetone (1: 1) with ice-cooling and stirring with 0.1 m

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Sodium meta-periodate added to the minimum amount of water, and the reaction mixture is stirred until the Precipitation of sodium iodate has ended. The mixture will filtered and the filtrate concentrated in vacuo. The residue is taken up in chloroform, filtered and concentrated in vacuo. Crude 5-Cp-methyls [] ilfiiiynbengamido) salicylic acid is obtained.

If you use two equivalents of metaperoodate and carry out the reaction at about 50 ° G
sulfonylbenaamido) salicylic acid «.

at about 50 ° G, 5-Cp-methyl-

If one apt Methylmere ο- the compounds of Examples 2 and 3i as described above oxidized _{9 s} are obtained the corresponding methylsulfinyl and Methylßulfonyl analogs

Example 11

5- (p-Oarboxybengylaminosalicylic acids

A solution of 0.05 M potassium hydroxide in 100 ml of water is made while stirring with 0.01 m 5- (p-CartoomethQxybenzylaBdno) -salicylic acid added and the resulting mixture gently heated to bring it into solution. The mixture is stirred at room temperature Filter for 5 hours * and adjust the pH of the filtrate with dilute hydrochloric acid. The 5 ~ (p-Carboxybenzylamino) salicylic acid is collected »

Example 12

5- (p-carbamylbenzylamino) salicylate

A mixture of 2 g of methyl 5- (p-cyanobenzylamino) salicylate in 25 ml of methylene chloride is added with stirring with 12 g

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Manganese dioxide added. The mixture is stirred for 70 hours at room temperature. The mixture is filtered and the cake is washed well with warm methylene chloride. The filtrate is concentrated in vacuo to a kickstand. The residue is chromatographed on a silica gel column using a methanol-methylene chloride system ( ^v / v 0-80% methanol) as the eluent. Methyl 5- (p-carbamylbenzylamino) salicylate is obtained.

The uritrile can also be obtained using concentrated < Sulfuric acid can be converted into the amide in the cold.

B e i a ρ i e 1 15

Heth yl-5- ("Df luorbenzamido) -o-anisate

If you methyl-5 ~ amiiio-o-anisate with p-fluorobenzoyl chloride reacted according to the procedure of Example 1, methyl 5- (p-fluorobenzene amido) -o-anisate is obtained.

If the other Benaoyl halides of Example 1 instead of p-fluorobenzoyl chloride in the one described above If the reaction is used, the correspondingly substituted one is obtained

Analogs.

If you methyl 5-amino-o-anisate with the aldehydes of the example 2 using the procedure of Example 2, the corresponding benzylideneaminoanisic acid derivatives are obtained.

If one uses the benzylideneaminoanisic acid derivatives according to the procedure of Example 3 reduced, the corresponding benzylaminoanisic acid derivatives are formed.

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Example 14

A solution of 2 g of 5- (p-Hydroxybenzylamino) salicylic acid 28 ml of acetic anhydride are added to 15 μl of pyridine and the mixture obtained is heated on the steam funnel for 5 hours, protected from moisture. When cooling down the mixture is added to 300 ml of water while stirring »the aqueous system is extracted well with chloroform, the chloroform layer is made with dilute hydrochloric acid and water, dried over magnesium sulfate, filtered and concentrated lia yakuum. 2-Acetoxy-5- (N ~. acetyl-p-acetoxybenzylamino) benzoic acid.

B ei ε ν ie 1

m ~ methoxymethylbenzoic acid

0.02M m-carbomethoxybenzyl bromide is added to 0.04M sodium methoxide in methanol and the mixture becomes several
Gently heated for hours. Water is added and the mixture is heated to boil off methanol, filtered and acidified with dilute hydrochloric acid. M-Methosymethylbenzoic acid is obtained.

Using potassium methyl mercaptide instead of sodium methoxide used in the reaction described above, m-Hethylthiomethyl! benzoic acid is obtained.

If you have m-carbomethoxybenzyl bromide with sodium benzylate or Converts potassium benzyl mercaptide and the product, as described above, hydrolyzed, m-benzyloxymethyl- and m-benzylthiomethylbenzoic acid are obtained.

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Eg game 15B -

5 cm - Metlio3cymethylbenzamido) - »salicic acid

2 g of m-methoxymethylbenzoic acid are gradually added to 20 ml of stirred thionyl chloride and gently heated until the reaction has stopped. The excess! Thionyl chloride is removed in vacuo · 30 ml of anhydrous benzene are added and then removed in vacuo to remove traces of thionyl chloride. The remaining m-methoxymethylbenzoyl chloride is used as it is for the reaction with 5-aminosalicylic acid used by way of the procedure of Example I 1. 5- (m-Methoxymethylbenzamido) salicylic acid is obtained.

If one uses m-methylthiomethylbenzoic acid, m-beiizyloxymethyl · «' benzoic acid and m-benzylthiomethylbenzoic acid from Example ■ 18 instead of m-methoxymethylbenzoic acid, as described above, used, one obtains 5- (m-methylthiomethylbenzamido) salicylic acid, 5- (m-Benzylo3cymethylbenzamido) salicylic acid or 5-Oa-benzylthiomethylbenzamido ^ salicylic acid.

Phosphorus pentachloride in phosphorus oxychloride can be used in place of thionyl chloride in the reaction described above will.

Example 16 Methyl 5 Cm-hydroxymethylbenz amido) -s alicylate

A mixture of 0.01 m methyl-5-Ca-benzyloxymethylbenÄ-amido) salicylate, 100 ml methanol and 0.5 g palladium (5 %) - on charcoal is at tree temperature in a hydrogen atmosphere (2.81 kg / cm) exposed and removed therefrom when 0.01 m of hydrogen has been absorbed, filtered

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and constricted in the Yjakiium. The residue is chromatographed on a silica gel column using an Ither-petroleum ether system ( ^v / v 5-90% ether) as the eluent. Methyl 5- (m ~ hydrosymethylbenaamido) salicylate is obtained

If one reduces methyl-5 ^ (a ~ toeniäyltMom € tl3iyl "ben2amido) - salicylate. _I as described above, one gets methyl-5- (mmercaptomethylbenzamidco-salicylat.

Example 17

Methyl-5- (ffi-amin om ^

0.01 m Met3byi-5- (p ~ eyano ^I ben23rlamino) ~ salicylate in -100 ml acetic acid are reduced at room temperature under a hydrogen atmosphere (2.81 kg / cm) using 0.5 S platinum oxide as a catalyst the theoretical amount of hydrogen has been consumed, the mixture is filtered and. the solvent removed in vacuo. The residue is taken up in chloroform ether, filtered and anhydrous, ethereal hydrogen chloride is added. The methyl 5 ~ (p-arainomethylbenzylamino) salicylate dihydrochloride is collected.

Example 18 .

Methyl 5- (p- dimethyl aminomethyl benzene ^

A mixture of 0.008M methyl 5- (p-aminomethylbenzylamino) salicylate, 6 ml 37% formaldehyde, 120 ml dried 1,2-dimethoxyethane, 50 ml glacial acetic acid and 2 teaspoons full of Raney-Uickel is treated with hydrogen (2.81 kg / cm) at room temperature. After the recording is over, the mixture will filtered and the cake washed well with fresh dimethoxyethane.

- 22 009882/2242

The combined filtrates are partitioned between sodium carbonate solution diluted with chloroform and the chloroform layer is dried and concentrated and the residue is ^{chromatographed on a silica gel column using a methanol-methylene chloride system (v} / v .0-90% methanol) as the eluent. Methyl 5- (p-dimethylaminomethylbenzylino) salicylate is obtained.

Example 19

Meth. Tl7 2-carbo3gy ~ 4- ( ¹ Pf luorbenzamido) ~ T> henyl carbonate

■■ ι

A mixture of 0.01 M 5- (p-fluorobenzamido) salicylic acid _f 0.02 M dimethylaniline and 30 ml benzene is mixed with 0.01 M methyl chloroformate over the course of 1 hour with constant shaking and cooling. After the odor is gone after chlorine _r carbönat, 100 ml (1 N) hydrochloric acid was added, and the mixture is filtered. The benzene layer is separated, dried, filtered and the benzene is removed in vacuo. Methyl 2-arboxy- ^ ~ (p-fluorobenzamido) phenyl carbonate is obtained.

Example 20

N- (* i ~ C arbo3 qy-4-hyd r oxyben z al) -ρ - fluo r aniline

If one 0.005 m 5 ~ ^F ormylsalicylsäure and p-3fluoranilin reacted as in Example 2 to obtain N- (3-Carbo2qy-4-hydroxybenzal) -pf luoranilin ..

If other substituted aniline compounds are used instead of p-fluoroaniline in the procedure described above, the corresponding substituted phenyliminomethylsalicylic acids are obtained.

- 23 -00 98 82/22 42

13 84-5
B_e_i_s.J5LA_fi_A_2.1A

A mixture of 0.015 m 5 "(] H ^ lworb @ nBylaiidno ^ salicylic acid and 50 ml of absolute methanol is slowly mixed with 2.0 ml of concentrated sulfuric acid while stirring. The mixture is then gently heated for 18 hours. Excess methanol is evaporated removed in vacuo and the back ~ was partitioned between chloroform-water distributed _β the chloroform "layer% 'ή.τά, washed with dilute Hatriumbicarbonatlosiing.und water, dried, filtered and concentrated" to give methyl • ^"ra 5 Cp ^flnoi>' b © ng; ylamizio) - »s.alic3rlat c

If msa the 5-Cp ~ ^ lüorbenzylaminQ) ~ salicylic acid in the "Procedure described above replaced by any of the other salicylic acid compounds according to the invention calibrate the corresponding methyl ester «,

When methanol "is replaced by other suitable alcohols, such as eth, snol, propanol, Xeopriopaiöl s butanol, isobutanol, 2-methoxyethanol or 2- l -thoxyethimol etc. etc., in the procedure described above, aicli also forms the corresponding ester",

Mas ο compounds, such as diasoiaethane, can also stir Eerstellurig the appropriate ester-s can be used and are prevented in some cases.

M- " (p-fluorobensylamino) -salicylamide

MWVMa ^ LAiWHAi MW w «i> i.- -Μ— -ir ι niiiiT 11 PIV η τ» «· ιι · 11 ι im ^ m Min in Ύ ■■■ ι.ι r τιτ ^ ι im hum ι.« ι. ιι </> .ι n jVt.m.i «» ι ι

A mixture of riethyl-4 ~ (p-fluorobenzene! 5ylaniino) -. Ealicylate and

009882/2242

BATH ORIGINAL

13 84-5

concentrated ammonium hydroxide (more than five times the excess) is left on in a sealed tube for 6 hours 100 ° C heated · After cooling, water is added and the 4 ~ (p-fluorobenzylamino) ~ salicylamide is collected.

If one uses monomethylamine, dimethylamine, ethylamine, diethylamine, Morpholine, piperidine etc instead of ammonium hydroxide used, the corresponding amides are obtained

B. Q i ..s - .. P _n . i_e 1, 2g

) salicylic at

A solution of 0.001 m barium hydroxide in 15 ml of water is treated with 0.001 m 5 ™ (p ~ ^ luorbenzaraido) salicic acid in ethanol
offset. The mixture is stirred and heated gently for 2 hours and the solvents are removed in vacuo
removed on a botation vaporizer. Sodium 5 - "(p-fluorobenzamido) salicylate is obtained.

If you have 1 equivalent of potassium hydroxide or sodium carbonate
Used instead of VGn. sodium hydroxide, the corresponding salt is formed.

If there are two equivalents of the bases given above

The examples given above are used to obtain the corresponding di-salt.

If you put 5- (p-plu.orbenzamido) ~ salicylic acid through, the other replaces salicylic acid compounds according to the invention one the appropriate salt.

- 25 -009882/2242

BAD ORIQjNAL

Claims (2)

13'84-5 June 24, 1970 ^ P a t e η t a-H s τ? return 1. j compounds of the formula in which: R is hydroxy, amino, lower alkoxy, lower alkylamino di-lower alkylamino _9, Diniedrigalkylaminoniedrigalkylamino, DiniedrigalkylaminoniedrigalkoiEy, Hydroxyniedrigalkosqf, Polyhydro3q7niedrigalko ^ r, Niedrigalkoxyniedrigalkoxy, Ehenylniedrigalkoaqy- _S pheno-sy, substituted ühenoxy, liedrigalkanoylaminoniedrigalkoxy, B ^ ydrazino, phenyl amino, morpholines, H-piperidino, pyrrolidino or Hydroxy-lower alkylaniino; Hg is hydrogen, acyl, lower alkyl or Alko3Eycarbonyl; IU hydrogen, halogen, halo-lower alkyl, medrigalkyl, Cyclone lower alkyl or alkoxy; X is hydrogen, lower alkyl, hydroxy, Sriedriga3.ko3iy, acyloxy, halogen, halo-lower alkyl, nitro, amino, lower alkylamino, di-edrigalkylamino, acylamino,. Mercapto, lower alkyl mercapto, lower alkylsulphinyl, lower alkylsulphonyl, sulfonamido, sulfinylamido _r amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, mercapton-lower alkyl, lower alkyl-mercapton-lower alkyl. Cyano, carboxy, carbalkoxy, carbamoyl, aryl, aralkyl, aryloxy or aralkoxy; Y ethyleneimino (-CH ₂ NH-), iminomethylene Ct - 26 009882/2242 Methyltdennitrilo (-.CH «N ~), bitrilomethylidene Il C-HsCH-), carbonylimino (-CiSH-) or iminocarbonyl O (-HH-C-), ■ with the proviso that the OK ^ group Btets ortho to the O '. d. C - R group stands. 2. Compounds of the formula in which: E Hy & rosey or üminoj Ep is hydrogen or lower alkyl; E-substance, lower alkyl or halogen; Σ hydrogen, medrigalkoxy, halogen, halogen-low alkyl or di-lower alkylamino; and Y !! ethylenimino («CH ^ HH-), iminomethylene (-MethyXidennitrilo (-OH-N-), nitrilomethylidene (- 0 ■. ' Carbonylimino (-CHH-) or iminocarbonyl (~ HHC ^); with the proviso that the GEp group is always ortho to the O C-E group. 3 x 4- (p-fluorobenzylideneamino) -balicylic acid. 4. 5 ~ (p-Fluorobensylamino) salicylic acid. - 27 - 009882 / 22A2 84-5 6. 4 ~ (p-Fluoraidlinomethyl) «- salicic acid 7-5 ~ (p 8. Process for the production of. ■ BenzyliÖGnamino ~ salicylic acids, characterized in that ® & η aminosalicylic acid with converts a substituted benzaldehyde » 9. The method according to claim 8 _? characterized in that said bensylideneamino-salicylic acids are reduced to benzylamino-salicylic acids » 10. Process for producing anilinomethylsalicylic acids, characterized in that a halomethylsali ~ cyclic acid reacts with a substituted aniline «, 11 · Process for the preparation of benzamidosalicylic acids, thereby marked ,, that one (a) a nitro anisole % u one. Amino anisole reduced? (b) said amino anisole with a benzoyl halide converts to a benzamidoanisole ^ (c) said benzamido anisole to a bensamidophenol deraethylated; and (d) said benzamidophenol from a benzamidosalicylic acid carboacylated. 12. Process for the preparation of rienyliminomethylsalicylic acids, characterized in that one forraylsalicylic acid with a substituted aniline. 13. Pharmaceutical agent, consisting of at least one - 28 -0 0 9-88-2 / 22.42 8 ^ -5. "'■■ * Member selected from the compounds of the formula in which: R hydroxy, amino, lower alcohol: xy, lower alkylamino, ■ Di-lower alkylamino, di-lower alkylamino-lower alkylamino, Di-lower alkylamino-lower alkoxy ', Hydroxy lower alkoxy, polyhydroxy lower alkoxy, lower alcohol, Phenyl-lower alkoxy, phenoxy, substituted phenoxy, lower alkanoylamino-lower dia3j: o3cy, Phenylamino, hydrazino, morphoiino, H-piperiföno, pyrrolidino or hydroxy-lower alkylamino; Bp hydrogen, acyl, lower alkyl or Alko ^ earbonyl; E · hydrogen, halogen, halo-lower alkyl, lower alkylj Cyclone lower alkyl or alkoxy; X water, lower alkyl, hydroxy, lower alkoxy, Acyli / iiy, halogen, halo-lower alkyl, kitro, amino, Lower alkylamino, di-lower alkylamino, acylamino, Mercapto, lower alkyl mercapto, ii lower alkyl sulfinyl, iiieirigalkylsulfonyl, sulfonamido, sulfinylataid ©, Amino lower alkyl, lower alkyl aniino lower alkyl, Diiiiedrigalkylamino-loweralkyl, Hydroxyniederigaiyyl, Alcohol lower alkyl »mercapton lower alkyl, Ifiiidrigalkylmercaptonlowalkyl »cyano, carboxy, Cnrbalkoxy, carbamoyl, aryl, aralkyl, aryloxy or AJ.'alkoxyj ■ ■ ■■ · 29-00988272242 ⁵ ^ d ORi _GiNAL 845 Methyl enimino (-CHgBH- ) ,, Iminometiiylea, Hethylidennitpilö (-CHnN-), " (-N-CH-), carbonylimino (-C- onyl (-HH-C with the the ο - one pharmaceutical. ouch 14. Pharmaceutical agent, member selected from ■ Formula '' e s in the mean H or Hydroscy Amis, © f. Hg hater substance or H _y X ¥ hydrogen on Hydrogen _s Ii alkyl - or I !! ethyleneimino, with the proviso « that dia 0 the C - B- pharmaceutically acceptable "KeHgöXc 009882/2242 15 · Compounds of the formula in the X means halogen, with the proviso that the Hydro group is always ortho to the carboxy group. 16. Process for preparing compounds of the formula COOH in which X is halogen, characterized in that one an ester of the formula where X is halogen and Ί is Hiedrigallcoxy, hydrolyzed. 009882/2242 ORIGINAL INSPECTED