GB1581443A

GB1581443A - Aminosalicylic acid esters

Info

Publication number: GB1581443A
Application number: GB13096/77A
Authority: GB
Original assignee: Mundipharma AG
Current assignee: Mundipharma AG
Priority date: 1977-04-01
Filing date: 1977-03-29
Publication date: 1980-12-17
Also published as: CH632670A5; FR2385685A1; PT66344A; FR2385685B1; NL7703373A; CA1113486A; GB1581444A; SE431936B; JPS53124232A; ATA214877A; SE7703296L; PT66344B; AT359648B; ATA739278A; DE2712934A1; AT351518B

Abstract

The preparation contains, as the active component, a novel o-, m- or p-aminosalicylic ester of the formula I <IMAGE> in which R is an alkyl radical having 1 to 18 carbon atoms in the chain or an alkenyl radical from the group comprising vinyl, allyl, undecenyl, oleyl and linolenyl, or the cyclohexyl radical, phenyl radical or menthyl radical, and the amino group is in the ortho, meta or para position. The novel compounds can be prepared by esterifying aminosalicylic acid or reducing a corresponding nitrosalicylic ester. The preparation is particularly suitable for use as a preparation for protection against sunburn.

Description

(54) NOVEL AMINOSALICYLIC ACID ESTERS (71) We, MUNDIPHARMA A.G. a Swiss Corporation organised under the Laws of Switzerland, of St. Alban-Vorstadt 94, Postfach, CH 40()6 Basel, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to novel aminosalicylic acid esters and a process for their production.

This invention therefore provides compounds of any of the general formulae

R represents an alkyl group containing from 1 to 18 carbon atoms. a vinyl. allyl.

undecenyl, oleyl or linolenyl group. or a phenyl, cyclohexyl or menthyl group, provided that in the case of formula (a). R does not represent a phenyl group a cyclohexyl group or an alkyl group containing 1 to 4. 6 or 1() carbon atoms. and in the case of formula (b), R does not represent an alkyl group containing 1 to 4 carbon atoms.

p-Aminosalicylic acid is a well known compound having a wide therapeutic use as a tuberculostatic agent and is capable of forming metallic salts and esters which are similarly employed in tuberculoses therapy. The phenyl ester of para-aminosalicylic acid is described in U. S. Patent No. 2.6()4, 488 (issued July 22 1952).

The esters of aminosalicylic acid may be prepared by the reduction of the corresponding nitrosalicylic acid ester. dissolved in ethyl acetate. using Raney nickel as a catalyst and hydrogen under pressure. The resultant yield of the respective aminosalicylic acid ester is excellent and the respective compounds are obtained as oils or white crystalline substances and may be purified by distillation under reduced pressure or crystallization. The respective esters of aminosalicylic acid are insoluble in water but soluble in alcohols. acetone, benzene, chloroform and vegetable oils.

When an alkyl or alkenyl ester of aminosalicylic acid is desired, then these may be prepared from either the alkyl-ortho. meta. or para-nitrosalicylate , said alkyl group may range from 1 to 18 carbon atoms in chain length and said alkenyl group may be a vinyl, allyl, undecenyl. oleyl or linolenyl group. The resultant alkyl aminosalicylate. wherein said alkyl group has from 1 to 18 carbon atoms in chain length may be purified by distiliation in vacuum (below 2mm. Hg. pressure) or by crystallization.

Those esters wherein the alkyl or alkenyl group is between l to 6 carbon atoms in chain length are oily or waxv in character and distil over at a temperature of below 18()"C at 2 mm.

Hg. Those esters in which the alkyl group is from 6 to 18 carbon atoms in chain length are obtained as solids, crvstallized from alcohol-water solution. The solid aminosalicylate esters are white crystalline or waxy substances. insoluble in water but soluble in the usual fatty solvents and alcohol.

The alkyl and alkenvl aminosalicvlic acid ester compounds described above were found to possess unique ultra violet screening properties by the well known spectroscopic method for determining the ultra-violet absorbing capacity of the compound. A standard reference to this method is "Organic Chemistry" by H. Gilman, Volume III, p. 127, et. seq., John Wiley and Sons, New York, (1953). In the evaluation of the ultra-violet absorption capacity of the compounds, the wave-length of the band of the maximum absorption is the important factor in determining whether a compound is suitable as an ultra-violet screening substance.

A useful means of expressing the degree of light absorption is the absorption co-efficient.

The ultra-violet absorption selections are determined spectrophotometerically utilizing the conventional ultra-violet spectrometer and an appropriate solution of the compound to be tested. The absorption co-efficient at the wave-length of maximum absorption designated as am,tX is an expression of the wave-length of maximum absorption and is calculated from the following formula relationship: a = - bc log To bc g To wherein a is the absorption co-efficient b is the thickness of the spectrophotometric cell in centimeters c is the concentration in grams per liter T is the amount of light passing through solution To is the amount of light passing through the solvent only in the same cell.

When this test was applied to the aforesaid compounds, it was found that the ultra-violet rays of the wave-length from 2950 A". to 3200 A". which have been shown to cause solar burning, evidenced by erythema, pain and skin edema, were effectively absorbed or blocked, while those ultra-violet light rays within the wave-length of between 3300 A". and 3800 A". (established to cause a desirable and beneficial tanning of the skin) were permitted to pass. Moreover, a preferred range of ultra-violet filtration occured between the wave-length of 346() A". and 38()0 A".. thereby selectively filtering the tanning rays from the solar burning rays in the ultra-violet spectrum. It was found that the aforesaid new compounds had an absorbance range of between 0.6 and 1 for the noxious ultra-violet burning rays within the wave-length of from 2850 A". to 3150 A"., whereas there was virtually no absorbance of the ultra-violet rays in the wave-length between 3460 A". to 3800 A".

Compositions comprising the sun screen compounds described above and other related compounds are described and claimed in our co-pending application No 7917533 (Serial No. 1581444).

The following examples illustrate the scope of the present invention but it is not intended to limit the invention thereby.

Example 1 In a suitable vessel containing 1 gm. mol of meta-aminosalicylic acid is added I gm. mol of phenol and 0.5 mol of pyrophosphoric acid. The mixture is stirred and auto-claved for one hour after which time it is poured into water. The solid material is filtered, suspended in acetone and neutralized with sodium hvdroxide to pH 6. Dilute ammonia solution is added to precipitate phenyl-m-aminosalicylate which is separated by filtration and dried.

The white crystalline powder is phenyl-m-aminosalicylate. melting between 158"C and 163"C.

In place of the meta-aminosalicylic acid described above. an equimolar quantity of ortho-aminosalicvlic acid may be substituted. The remainder of the steps are the same and the resultant compound is phenyl-ortho-aminosalicylate.

Exaowlple 2 One-tenth mol of alkyl-m-nitrosalicylate is dissolved in 250 ml. of ethvl acetate and 10 gms. of Raney nickel added. The mixture is placed in a suitable container to permit pressure hydrogenation and hydrogen gas is passed into the solution. When the gas pressure reaches 10 pounds psi. at S() C. the mixture is agitated and when the absorption of hydrogen has reached equilibrium. it is shaken for four hours and cooled. The mixture is filtered and the alkyl-m-aminosaliQvlite formed is isolated bv distillation at 2 mm. Hg.

pressure.

The alkyl-m-nitrosalicylate may be any appropriate alkyl-nitrosalicylate ester selected from the group consisting of alkyl-ortho-nitrosalicylate compounds wherein said alkyl group is from I to 18 carbon atoms in chain length. alkvl-mcta-nitrosalicylate compounds, wherein said alkyl group is from 5 to 18 carbon atoms in chain length and alkyl-pnitrosalicylate wherein said alkyl group iS from 5 to 18 carbon atoms in chain length. The remainder of the steps are the same and the respective ortho. meta or para-aminosalicylate alkyl ester is obtained.

Example 3 One-tenth mol of an alkali metal salt of para-aminosalicylic acid as for example, sodium-p-aminosalicylate, potassium-p-aminosalicylate or lithium-p-aminosalicylate, is dissolved in 300 ml. of alcohol and to this is added exactly one-tenth mol of a menthyl halogen salt as for example, menthyl chloride, menthyl bromide or menthyl iodide. The mixture is stirred and 0.5 gms. of freshly precipitated silver hydroxide is added as a catalyst.

The mixture is warmed to 50"C. for a period of at least two hours, cooled to room temperature and filtered. The filtrate is set aside to crystallize in an ice-chest and menthyl-para-aminosalicylate is obtained as a white crystalline substance melting at 187"C.

to 1890C. The compound is insoluble in water but soluble in alcohol, benzene and chloroform.

In place of the alkali metal-para-aminosalicylate salt described above, there may be substituted in equivalent molar quantities, an alkali metal-ortho-aminosalicylate or an alkali metal-meta-aminosalicylate. The remainder of the steps are the same and the formed compound obtained is the respective menthyl-ortho-aminosalicylate (mp. 201"C. - 206"C.) or menthyl-meta-aminosalicylate (mp. 173"C. - 178"C).

Example 4 In place of the menthyl chloride described in Example 3, there may be substituted equimolar quantities of cyclohexyl chloride, cyclohexyl bromide or cyclohexyl iodide. The remainder of the steps are the same and the resultant compound formed is the respective cyclohexyl-para-aminosalicylate, cyclohexyl meta-aminosalicylate and cyclohexyl ortho aminosalicylate.

Example 5 To a solution of 0.5 gm. mol of alkali metal para-aminosalicylate salt, as for example the respective sodium, potassium or lithium salts dissolved in 500 ml. of ethanol is added 0.5 gm. mol of undecenyl chloride. The mixture is stirred and warmed to about 60"C. for at least four hours. The separated sodium chloride is filtered and the alcohol solution set aside to crystallize. A white waxy solid is obtained which melts between 80"C. and 850and is undecenyl para-aminosalicylate.

In a similar manner, equimolar concentrations of vinyl chloride, allyl chloride. oleyl chloride, linolenyl chloride, vinyl bromide, allyl bromide, undecenyl bromide, oleyl bromide, linolenyl bromide, vinyl iodide, allyl iodide, undecenyl iodide, oleyl iodide or linolenyl iodide may be used in place of the undecenyl chloride described above and the respective formed alkenyl p-aminosalicylate ester is obtained.

In place of the metal-para-aminosalicylate salt described above there may be substituted in equimolar proportions a metal-meta-aminosalicylate salt or a metal-orthoaminosalicylate salt, said metal being sodium, potassium or lithium or ammonium. The remainder of the steps are the same and the respective formed alkenyl meta-aminosalicylate ester and alkenyl ortho-aminosalicylate ester described above is obtained.

WHAT WE CLAIM IS: 1. A compound of any of the general formulae

in which R represents an alkyl group which contains from 1 to 18 carbon atoms, a vinyl, allyl, undecenyl, oleyl. or linolenyl group or a phenyl. cyclohexyl. or menthyl group,

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. alkyl ester is obtained. Example 3 One-tenth mol of an alkali metal salt of para-aminosalicylic acid as for example, sodium-p-aminosalicylate, potassium-p-aminosalicylate or lithium-p-aminosalicylate, is dissolved in 300 ml. of alcohol and to this is added exactly one-tenth mol of a menthyl halogen salt as for example, menthyl chloride, menthyl bromide or menthyl iodide. The mixture is stirred and 0.5 gms. of freshly precipitated silver hydroxide is added as a catalyst. The mixture is warmed to 50"C. for a period of at least two hours, cooled to room temperature and filtered. The filtrate is set aside to crystallize in an ice-chest and menthyl-para-aminosalicylate is obtained as a white crystalline substance melting at 187"C. to 1890C. The compound is insoluble in water but soluble in alcohol, benzene and chloroform. In place of the alkali metal-para-aminosalicylate salt described above, there may be substituted in equivalent molar quantities, an alkali metal-ortho-aminosalicylate or an alkali metal-meta-aminosalicylate. The remainder of the steps are the same and the formed compound obtained is the respective menthyl-ortho-aminosalicylate (mp. 201"C. - 206"C.) or menthyl-meta-aminosalicylate (mp. 173"C. - 178"C). Example 4 In place of the menthyl chloride described in Example 3, there may be substituted equimolar quantities of cyclohexyl chloride, cyclohexyl bromide or cyclohexyl iodide. The remainder of the steps are the same and the resultant compound formed is the respective cyclohexyl-para-aminosalicylate, cyclohexyl meta-aminosalicylate and cyclohexyl ortho aminosalicylate. Example 5 To a solution of 0.5 gm. mol of alkali metal para-aminosalicylate salt, as for example the respective sodium, potassium or lithium salts dissolved in 500 ml. of ethanol is added 0.5 gm. mol of undecenyl chloride. The mixture is stirred and warmed to about 60"C. for at least four hours. The separated sodium chloride is filtered and the alcohol solution set aside to crystallize. A white waxy solid is obtained which melts between 80"C. and 850and is undecenyl para-aminosalicylate. In a similar manner, equimolar concentrations of vinyl chloride, allyl chloride. oleyl chloride, linolenyl chloride, vinyl bromide, allyl bromide, undecenyl bromide, oleyl bromide, linolenyl bromide, vinyl iodide, allyl iodide, undecenyl iodide, oleyl iodide or linolenyl iodide may be used in place of the undecenyl chloride described above and the respective formed alkenyl p-aminosalicylate ester is obtained. In place of the metal-para-aminosalicylate salt described above there may be substituted in equimolar proportions a metal-meta-aminosalicylate salt or a metal-orthoaminosalicylate salt, said metal being sodium, potassium or lithium or ammonium. The remainder of the steps are the same and the respective formed alkenyl meta-aminosalicylate ester and alkenyl ortho-aminosalicylate ester described above is obtained. WHAT WE CLAIM IS:

1. A compound of any of the general formulae

provided that in the case of formula (a) R does not represent a phenyl group, a cyclohexyl group or an alkyl group containing 1 to 4, 6 or 10 carbon atoms, and in the case of formula (b) R does not represent an alkyl group containing 1 to 4 carbon atoms.

2. Vinyl-para-aminosalicylate.

3. Allyl-para-aminosalicylate.

4. Undecenyl-para-aminosalicylate.

5. Oleyl-para-aminosalicylate.

6. Linolenyl-para-aminosalicylate.

7. Menthyl-para-aminosalicylate.

8. Methyl-ortho-aminosalicylate.

9. Ethyl-ortho-aminosalicylate.

10. Propyl-ortho-aminosalicylate.

11. Isopropyl-ortho-aminosalicylate.

12. Butyl-ortho-aminosalicylate.

13. Decyl-ortho-aminosalicylate.

14. Vinyl-ortho-aminosalicylate.

15. Allyl-ortho-aminosalicylate.

16. Undecenyl-ortho-aminosalicylate.

17. Oleyl-ortho-aminosalicylate.

18. Linolenyl-ortho-aminosalicylate.

19. Cyclohexyl-ortho-aminosalicylate.

20. Menthyl-ortho-aminosalicylate.

21. Decyl-meta-aminosalicylate.

22. Vinyl-meta-aminosalicylate.

23. Allyl-meta-aminosalicylate.

24. Undecenyl-meta-aminosalicylate.

25. Oleyl-meta-aminosalicylate.

26. Linolenyl-meta-aminosalicylate.

27. Cyclohexyl-meta-aminosalicylate.

28. Menthyl-meta-aminosalicylate.

29. Phenyl-ortho-aminosalicylate.

30. Phenyl-meta-aminosalicylate.

31. A process for the preparation of a compound as claimed in any of claims 1 to 30 by reduction of the corresponding nitro-salicylic acid ester.

32. A process as claimed in 31 in which the reduction is carried out in solution in ethyl acetate.

33. A process as claimed in claim 31 or 32 in which the reduction is carried out using hydrogen in the presence of Raney nickel as catalyst.

34. A process for preparing a compound as claimed in any of claims 7. 19, 20, and 27 to 30 comprising the steps of: a) mixing aminosalicylic acid with phenol. menthol or cyclohexanol.

b) adding pyrophosphoric acid and heating. and c) recovering the ester.

35. A process for preparing a compound as claimed in claim 1 in which R represents an alkyl group which comprises the steps of: a) dissolving in ethyl acetatc. the corresponding alkyl ester of nitro-salicylic acid, b) adding Raney nickel hydrogenation catalyst.

c) hydrogenating at 1() pounds psi hydrogen gas pressure at 8()"C..

d) cooling. filtcring and recovering therefrom the alkyl amino-salicylate ester formed.

36. A process for preparing a compound as claimed in claim I in which R represents an alkenyl group comprising the steps of: a) dissolving in alcohol an alkali metal or ammonium salt of amino-salicylic acid, b) adding an approximately molar equivalent quantity of the corresponding alkenyl halide, c) adding a catalytic quantitv of freshly precipitated silver hvdroxide, and d) recovering the formed alkenyl ester of aminosalicvlic acid therefrom.

37. A process as claimed in any of claims 31 to 36 substantially as herein described with reference to any of the examples.

38. A compound as claimed in any of claims 1 to 30 which has been prepared by a process as claimed in any of claims 31 to 37.