DE3148424A1 - Novel 2-hydroxy-5-(2',4'-difluorophenyl)benzoic acid derivatives, process for their preparation, use as pharmacologically active substances and pharmaceutical preparations which contain these derivatives - Google Patents

Description

New 2-hydroxy-5- (2, 4 -difluorophenyl) -benzoic acid derivatives, Process for their production, use as pharmacologically active substances and pharmaceutical Preparations containing these derivatives.

The invention relates to new 2-hydroxy-5- (2 ', 4' · - difluorophenyD-benzoic acid derivatives, on processes for the preparation of these derivatives, on their use as active substances; substances in pharmacological preparations and on pharmaceutical tables Preparations containing these derivatives.

In particular, the invention relates to compounds having the following structural formula

wherein R is hydrogen or an oxycarbonyl radical of the form

-C-O-X

II

in which X can be a straight or branched alkyl group with 1 to 6 carbon atoms, phenyl, benzyl, (C _5-7 ) cycloalkyl, 2,2,2-trichloroethyl or 2,2,2-tribromethy1. .

Examples of the alkyl groups given here are: methyl, ethyl, propyl, isopropyl, η-butyl, sec. Butyl, iso-

O O 6

3U3..2 /.

butyl "tert". Butyl, n-pentyl, isopentyl, heopentyl, n- ■ hexyl, "2,3-diraethylbutyl, -2-methylpentyl «Ad 3-methylpentyl.-

• A © preferred © group © before connections are the connections nach'der formula I, ia where R is hydrogen, a straight line or branched® alkyl group with 1 to 4 carbon atoms or B @ nzyl,

Di © substance 2-hydroxy ~ 5- (2 ^8, 4 ^th difluorophenyl) benzoic than- those known ι cf. "äazu example, British Patent Specification 1,175,212, South African © Patent 67Ό1Ο21, French Patent 1,522,570, German Patent 1618 663 uni Deutsche Auslegeschrift 2 532 559, OS patents 3 574 870 and 3 681 44 5.

The biological properties of this compound are described by J.-Hannah et al. In Brit.Journ.Clin.Pharmacol, 4_, 75-135, 1977 and PW Majeurs et al. In Brit. Journ. Clin. Pharmacol., £, 155-185, 1977 and by other authors. The erfindungsg © saä®en compounds can be prepared by various ■ @ n the process hersteilen, the Sun is essentially determined by the final products to be obtained Sinoe _P. © general method for Syathetisierwag the compounds of the formula I obeagenasmtoiÄ for example, that the S-Ca ■ ^1, 4 '' äifluorpheiayl) benzoic acid according to the formula

III

An organic halogen carbonate is used

^ lP 1 ^ 3 # * ti ^ # *** '

ι ■ * *

'ό Ί 4 b k

in which Y is a halogen atom and X is as defined above, so that a compound of the formula

results in which X is as defined above; afterward the reaction is carried out with the 2-methoxyphenol according to formula VI, so that compounds according to the above formula I result, in which R is the group -C-O-X and X has the structure indicated above. 0

The sequence of reactions can be illustrated by the following scheme

COOH

+ Y-C-O-X

■ * P

III

IV

; ν

ν +

VI

OCH.

VII * Compounds of the formula I, where R »-C-O-X 0

If X is 2,2,2-trichloroethyl or 2,2 * 2-tribroraethyl, the compound according to the above formula VII can undergo selective hydrogenolysis, whereby the group -C-O-X is replaced by a hydrogen atom, so that. 0 gives the compound of formula I, wherein R is hydrogen.

In practical use, a molar proportion of the compound of the formula III is reacted with 2 to 4 molar equivalents of a compound of the formula IV, preferably a compound in which Y is chlorine; the temperature is between about -10 ° C. and room temperature _s and the reaction time is about 10 to about 40 minutes, preferably 15 to 30 minutes Acetone, methyl ethyl ketone, diethy! Ketone and related solvents, and in the presence of a tertiary organic nitrogen-containing base, for example trimethylamine, triethylamine, pyridine, in pycolines and the like, so that the acidity which develops during the reaction is neutralized. The result is a compound according to formula V which, if necessary, is isolated and determined, but which can also be used as such for the next step. This compound is thus brought into contact with a slight molar excess (calculated according to the starting compound of Formula III) of the 2-methoxyphenol according to Formula VI; the reaction temperature is between about -10 ° C. and about room temperature, the reaction time is about 3 to about 8 hours, so that a compound according to formula VII is obtained, which is isolated and determined by methods known to the person skilled in the art.

As mentioned * the compounds of the formula VII form with X = »2,2,2-trichloroethyl or 2,2,2-tribroraethyl are also useful Intermediate connections to obtain the connection

BS

- 10 -

according to formula I, in which R is hydrogen, via a selective hydrogenolysis, by which the group -COX is replaced by a hydrogen atom. This hydrogenolysis is carried out in the usual way, for example with zinc and acetic acid in diethyl ether or catalytically with PtO ₂ or palladium / activated carbon as catalysts.

The compound of formula I with R = hydrogen leaves win by another method, with only a molar proportion of the compound of the formula III with between about 3 and about 7, preferably with about 5 molar equivalents of the compound of formula VI in the presence of catalytically effective amounts of a strong acid, such as sulfuric or p-toluenesulfonic acid, is brought into contact. the The reaction takes place in an inert atmosphere at the melting temperature of the reaction mixture, that is to say in the absence of any reaction solvent , and the course of the reaction is continuously monitored by thin-layer chromatography until the spots corresponding to the initial reagents disappear.

The compounds according to the invention can be used as pharmacologically active substances. They have remarkable anti-inflammatory, antipyretic, analgesic and phlegm-promoting properties. The anti-inflammatory, antipyretic and analgesic properties develop at doses which, expressed in mg / kg, seem to be higher than those determined for the reference substance 2-hydroxy-5- (2 ¹ , 4'-difluorophenyl) -benzoic acid, but are if they are correctly expressed in mmol / kg, completely comparable or, better said, of the same order of magnitude as that for the reference substance mentioned. But apart from that, the substances according to formula I have particularly clearly expectorant properties, while these properties in the 2-hydroxy-5- (2 *, 4'-difluorophenyl) benzoe-

ä oo at t O 1 / O / 0

oo a. a .ο · j I t (: j I] ^

»9 1

a 6 a

- 11

acid could not be detected »Finally there is to point out * that the connections according to the invention Very low levels of toxicity, such as themselves clearly shown in Table 1, so that the corresponding therapeutic indices, i.e. the respective values of the ratio between the toxic and the effective Dose, even cheaper than the already high thera-. peutic index of the reference compound, and is known to be a high therapeutic index is a strong indicator of the potential safety of a drug.

The following table 1 _{lists the LD 50} values obtained on mice according to Lichtfield and Wilcoxon, Journ. Pharm.Expt.Ther., 9 £, 99, 1949, the chemical-physical properties and the minimum doses to be observed for an anti-inflammatory, antipyretic, pain-relieving and expectorant effect, determined in accordance with the tests of the compounds according to the invention described below.

The anti-inflammatory properties were examined with the aid of the carrageenan edema test on rats (730 male Sprague, Dawlex rats with an average weight of 150 g) according to the procedure in CA. Winter et al., Proc. Soc. Exptl. Biol. Med., 211 » ⁵⁴⁴ * 1962. Table 2 shows representative results obtained with the compound according to Example 3 in comparison with 2-hydroxy-5- (2 ¹ , 4'-difluorophenyl) benzoic acid.

The analgesic activity was studied by the test of Randall and Selitto, "according to which a pressure was applied to the hind paw of the rat, which had previously been brought by injection -from brewer's yeast to inflammation; the increase in the pain threshold was recorded. Representative © results with the compound according to Example 6

4 Ö A- Z 4

I "T V ^ * T i- T

compared to 2-hydroxy-5- (2 ', 4'-difluorophenyl) benzoic acid are shown in Table 3.

Also the test with induced hyperpyrexia on rats (165 male Sprague Dawley rats of average 200 g weight) caused by intramuscular administration of brewer's yeast, proved that the activity of the compounds according to Examples 3, 5 and 6 is very remarkable is: namely, the dose shown in Table 1 resulted in 1, 2 and 4 hours after the administration measured temperature decrease of about 1 ° C.

The values recorded in Table 4 relate to "representative tests on rats according to EM Boyd and GM Johnston, Am. Journ. Med. Sci., 199 , .- 246, 1940j and 201 , 810, 1941; the properties of the The figures clearly show that the compounds according to Examples 3, 5 and 6, in contrast to the reference compound 2-hydroxy-5- (2 ', 4'-difluorophenyl) benzoic acid, show a clearly noticeable increase in the water content in the upper Caused respiratory tract, thus the stimulating effect of the compounds mentioned on the secretion of the respiratory system has been proven: The compounds according to Examples 1, (2) and 4 show corresponding properties, but to a lesser extent.

Table 1

Θ 6 #

β Ο β

3Η3424

- 13 -

Tabel

Chemical-physical properties, LDc _{or similar}

mg / kg oral) and lowest effective dose (mg / kg oral) *

Connection according to the example

Melting point

^LD 50 mice

Lowest effective dose (rats)

entztin- flebersen- painful thinkers
inhibiting effect
effect

alleviate litter. promot. Effect effect

1.2 3

4 5

105-6> 1300 **

oil 1050
438 40
20th 103-6 > 135Ο »· > 50 78-79 970 35 90-92 1200 • 35

50

70 2! 00 40> 4Ο0

50

> 50 ***

70 200 70 200

Lowest doses at which there were significant differences (P <0.01) between the response of the treated groups and the response of untreated (control) groups. "

Zero mortality at the indicated doses.

no clear effectiveness up to the specified doses.

Table 2

* · ♦ · ■ «» ψρ

9 ** 99 ο ecta

»» Ff · ■ · * t j

- 14 - ■

Table 2

Activity of the compound according to Example 3 and of 2-Hydroxy-5- (2 ', 4'-difluorophenyl) benzoic acid in Carrageenan edema test on rats (240 male Sprague Dawley? · Rats, 30 rats per group in 8 attempts)

Connection after

example

Dose mg / k, g oral

% Reduction in induced edema compared to control groups

Statistical Significance

3 - 20th -27 n.s. · 40 -51 λ <0.01 60 -70 ' <0.01 80 -80 ... - - <U _e Di

2-hydroxy-10

5- (2 \ 4 ^f -. 20

difluoro- 30

phenyl) - 40 benzoic acid

-24

■ 55
-68 -84

n.s. <0.01 <0.01 <0.01

n «s ·

»Β« I)

a 3> ο «ο

O ßß ΰ

WHERE * OVER

- 15 -

3 U 8 ' 2 U

»Ο O

Table 3

Pain-relieving effect of the compound according to Example 6 and of 2-hydroxy = 5- * (2 ', 4' ~ aifluarphenyl) benzoic acid in the Randall and Selitto test

Conn- dose number of
dung according to mg / kg rats
Example oral

Sensitive to pain-% increase in threshold (g) pain threshold of the inflamed versus Kon-paw (**) troll groups

6th 40 30th 127. 2 29 8th . 60 30th 139! ' 9 ■ 42. 80 ■ 30 155. ' 8th 9 (**) 2-hydroxy 20th 30th 124 » 8th 27 5 difluoro- 30th
40 30th
30th 141 ο 7 ' 55. 8 (** h) phenyl) - ■ benzoic acid Control (D) 30th 98 + β i.2 _ groups «As

The control animals were orally administered 10 mg / kg of peanut oil

Average of three attempts

Means after 1 and 2 hours after administration of the substances

Statistically significant® values for the control groups

<0.01) compared to

Y I 4 Ö 4- Z

- 16 -

Table 4

Water content (in mg) of the trachea of Sprague Dawley rats, orally treated with Physiological Solution and the compounds of the invention. Comparison connection: 2-hydroxy-5- (2 ·, 4'-difluorophenyl) benzoic acid

Increase in dose number of mean water increase according to mg / kg rats (*) aerean content in% example oral (mg) versus

Kontro11 groups

1.2 400 40 93 + 8.5 10. 9 n.s. 3 300 40 140 + 11.3 65. 6th <0.01 4th 400 40 98 + 11.6 ■ 11. 5 n.s. 5 250 40 142 + 13.1 67. 1 <0.01 6th 300 40 135 + 15.3 58. 8th <0.01

2-hydroxy

difluoro (phenyl) benzoic acid

Physiological solution

400

40 86 + 9.3

10- ml -40 -55 + 6.8 · ..

() Average of four experiments
ns not significant

O β. Ο «

,. "..: ■ 3U8424

it τ * at »

D β α α V O

0β a * *

- 17 -

The use of the compounds according to the invention extends on all ways and means of use, including incorporation of the compounds in pharmaceutical preparations.

Thus, in the method of using the compounds of the invention, the active ingredient can be used directly or administered as an effective component of pharmaceutical formulations for oral, parenteral or rectal administration will. For oral administration, for example, the compounds are in tablets, capsules, sugar-coated Tablets, dispersible powders, lozenges, syrups, elixirs or the like installed. The preparation to be taken orally can contain at least one of the usual auxiliary substances, for example means for sweetening, flavoring, coloring, Coating and preserving, so that a pleasant-looking and tasty preparation is created. For parenteral Use, the compounds according to the invention are incorporated into pharmaceutical preparations that are for intravenous or intramuscular administration, for example in vials or ampoules. The active substance is thus brought into an injectable administration form which is known per se and which also contains the suitable dispersing, Moisturizing, suspending and buffering substances records.

For rectal administration, the active ingredient is preferably incorporated into suppositories. The formulation the suppositories are also carried out in a manner known per se; they contain the active substance mixed with the common drug carriers, such as wax, Whale fat, sesame oil, gelatine, peanut oil or mixtures of the substances mentioned.

When using the compound according to the invention

- 18 -

these are administered at a daily dose between about 5 to about 25 mg / kg of body weight. The forms of the pharma-temporal Dosages contain the active principle in amounts that vary between about 350 mg and about 1700 mg, and they can be given once or several times a day.

These include common, but not limiting, pharmaceuticals Dosage forms and amounts of administration communicated:.

- Tablets: about 400 to about 1000 mg, twice or

more than twice a day

- Suppositories: about 700 to about 1500 mg, twice or

more than twice a day.

The following examples serve to better understand the invention; they are in no way intended to limit the scope of the invention.

Example It

2-Hydroxy-5- »(2 '*. , 4' -difluorophenyl) benzoic acid, ester with 2-methoxyphenol (formula I with R = H)

A mixture of 25 g (0.1 mol) of 2-hydroxy-5- (2 ·, 4'-difluorophenyl) Benzoic acid, 62 g (0.5 mol) of 2-methoxyphenol and 0.5 to 1 g of p-toluenesulfonic acid were added in an inert atmosphere melted until a clear, homogeneous liquid resulted. The course of the reaction was determined by thin layer chromatography (Merck F-j- ^ - silica gel plates; eluent: anhydrous Benzene; Visualization of the stain: UV light 254 nm). After the reaction was considered to have ended, the the molten mass is cooled and passed through a silica gel column (Merck 60 silica gel; mean particle size: 230 - 400 mesh) given and eluted with anhydrous benzene.

3U8424

The fractions with a uniform spot and R _f = 0.70 were collected, the benzene was evaporated off in vacuo so that an oily residue remained, which solidified after standing for several hours and recrystallized from diisopropyl ether

was sated. Melting point 102 to 103 ° C.

Elemental analysis on

expected

.measured

Molecular weight: 356.33 ic ■% η

67.41 3.97

67.42 4.04

Infrared spectrum (in GHClj solution) characteristic absorption bands at frequencies 3230,

1700, 1600 to 1620 cm

"" ¹

Nuclear Magnetic Resonance (in CDCI3) % characteristic

Resonans peaks at the following 6 (ppm? Internal standard: TMS): 3.77 (s, 3H)? 6.67 - 7.77. (m, 9H); 8.17-827 (m, 1H); 10.57 (s, 1H). s β singlet, m = »multiplet.

Example 2

2-hydroxy-5- (2 ', 4' -difluoropheny-ubenzoic acid, Ester with 2-methoxyphenol (formula I with R = H)

5g (0.020 mol) of 2-hydroxy-5- (2 ', 4'-difluorophenyl) benzoic acid and 4 g (0.039 mol) of anhydrous triethylamine were dissolved in 58 ml of anhydrous methyl ethyl ketone. After cooling down at temperatures below 0 ° C. the reaction solution became ' dropwise © sait 8.4 g (0.039 mol) of 2,2,2-trichloroethylechlorocarbonate added, the temperature was kept below 0 ° G for 15 to 30 minutes, with a precipitate of tri-ethylamine hydrochloride originated. Make addition of a solution

of 3.6 g (0.029 mol) of 2-methoxyphenoT in 40 ml of the same anhydrous lower aliphatic ketone as above, the temperature was raised to room temperature, then the reaction solution was stirred for several hours and the insoluble residue was filtered off. The resulting solution was evaporated to dryness under reduced pressure, and the remaining oily residue was taken up in methylene chloride. The organic solution was washed first with 5% dilute hydrochloric acid and then with 5% dilute sodium hydroxide solution and finally with water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo, so that an oily residue was obtained Thin-layer chromatograph! See analysis (Merck F ₂₅ 4 -silica gel plates; mobile phase: anhydrous ethyl acetate; visualization of the stain: UV light 254 nm) showed a main stain and traces of the starter acid.

This residue solidified on standing under cooling; it was made several times from a lower aliphatic alcohol, preferably absolute ethyl alcohol, crystallized out. Melting point 121 to 124 ° C. The product corresponds to a Compound of formula I in which R is the radical 2,2,2-trichloroethoxycarbonyl is: 2- (2,2,2-Trichloräthoxycarbonyloxy) r5- (2 *, 4'-difluorophenyl) benzoic acid, EstermLt 2-methoxyphenol ..

Elemental analysis for 023H-CF ₂ CIjP ₆ : Molecular weight: 530.71

% C '% H

calculated 51.95 2.84 measured 52.16 2.84

Hydrogenolysis of this compound was carried out by known methods: for example either by dissolving of the product in diethyl ether with glacial acetic acid and addition of zinc dust or by catalytic hydrogenation in the presence of platinum dioxide or palladium / activated carbon.

ο «O Ö P up Qo ο

dt} * 9 ο- β «e Q

O- c ■ · β Q

- 21 -

"The end product was then isolated according to known methods. The oily residue obtained was left to stand until it had hardened and was recrystallized as a diisopropyl ether or diethyl ether / light petroleum. Melting point 105 to 106 ° C."

The chemiseh-physicalisehs eigease adherence a -are the same as with the connection created according to example 1 »

Example 3-

2- (BensyloxycarbonfloxyJ-S ^ Ci ⁹ , 4 '= ciifluorophenyl) - "b © nzoic acid, ester with 2-methoxyph © nol (Formula 1,

Κ 2 \\
O

A solution of 8 g (O _p O32 mol) of 2-hydroxy-5- (2 '"4'-difluorophenylbenzoic acid and 8 g of CO (.079 mol) of anhydrous triethylamine in 112 ml of anhydrous lower aliphatic * ketone was below 0 ° C abgekühltι then vrarde within 15 min a 50% igs solution of 26 ^ 9 g of benzyl chlorocarbonate was added After Beeadigang the addition, the Reaktionsgemiseh gorütet UNOE € afe © i iäim © s was maintained below 0 ° C '(O O79 _mol?).? - then sehn® !! © was ine solution of 4 g (0.032 mol) of 2-Methossyphenol in 16 ml of the same anhydrous lower aliphatic ketone stated _# would already used above, iilach several hours of stirring at room temperature under constant monitoring of the course of the reaction by thin layer chromatography (Iferck FgEA ^ SiX-ikagelplatten; mobile phase: anhydrous ethyl acetate, visualization of the stain with UV light ο 254 naai S ^ of the product s Q (, 82) the solvent was evaporated off under reduced pressure, an oily residue resulted which was replaced by a silica gel acid (Merck 60 Silica gel (medium size 230 to 400 mesh) was added and eluted with a 1 s 1 (volume) chloroform / n-hexane mixture.

The fractions with a uniform stain were collected, dried; the residue was a colorless, pure one oil. . .

Elemental analysis for ^C 28 ^{H 2O F} 2 ^O 6 ' ^M ° l ^e k ^u l ^ar 9 ^ew i ^cnt: 490.47

% C% H% F calculated 68.57 4.11 7.75 measured 68.36 3.99 7.90

Infrared spectrum (pure liquid compound): characteristic absorption bands were shown at the frequencies 1765, 1700 cm ".

Nuclear magnetic resonance spectrum (in CDCl ^): Characteristic resonance peaks were found at the following S (ppm; internal standard: TMS): 3.70 (S, 3H); 5.17 (s, 2H); 6.55 to 8.33 (m, 15H).
s »singlet; m = multiplat.

Example 4

2- (Methoxycarbonyloxy) -5- (2 ', 4'-difluorophenyl) benzoic acid, ester with 2-methoxyphenol (formula I with R β CO-CH ₃
0

The compound given in the name was prepared essentially as given in Example 3: from 2-hydroxy-5- (2 ', 4 * -difluorophenyl) benzoic acid, methyl chlorocarbonate and 2-methoxyphenol. The end product sought was in the form of a dense oil that did not contain any chromatographic Required cleaning as it hardened on standing. It was made from diisopropyl ether (melting point 102 to 106 ° C) recrystallized and there was a product with R-β 0.85 (same conditions as in Example 3).

0 0 6 O ΰΟ O (J * O ttQ

DoOO O's Ho- ΰ

CöOOt? O £> Ο0ί) O

S δ Λ 6 OO ft t? ϊ.

on C ^ ₉ H- ^ F ^ Ofi * Mol © kuXarg © vJichts 414,37

SC Ώ H% I · '

63.77 3.89 9.14

IafrarotspektruiB (nujol) s characteristic absorption bands occurred & nf at the frequencies

Kernmag netls ches Rssonaagg gekt-riam (in CDCl,) s characteristic - - - stisch © Essoaaaspeaks occurred

followingdn ο Cppa «internal standard: TMS) s? S ₁₇ SS (@, 3H) j 6 ^ 5 to 8.4

β α SInglett? m <= multiplet.

2- (Isobutylojsycarbonylosy) -5 ~ (2 ' _ff 4' = difluorophenyl) benzoic acid , ester with 2 ~ I-ä @ thoxyphenol (formula I

The in the title genaaat © compound uurde. Essentially as -in Example 3 aagegebea prepared § from 2-Hydroxy- -5- (2 ⁹ "4" -diflworphsnyDbeasoQsaur ©, isobutyl chlorocarbonate iaad 2-M @ thojsypfeoB © lo Di © önfQSOlaigtQ compound if the column was cleaned (cf. example 3) -, the fractions with @iah @ itliefeem stain with R _f = 0.84 were collected

B @ standing, the product was Feist, and it was recrystallized from absolute ethyl alcohol ο 7S melting point to 78 ° C ₀

Elemental analysis on ^C 25 ^H 22 ^F 2 ° 6 ^{? Molecular} weight: 456.46

% C% H% F calculated 65.78 4.85 8.32 eaten 65.62 5.06 8.34

Infrared spectrum (nujol): characteristic absorption bands appeared at the frequencies 1770, 1750 cm " ¹ .

Nuclear Magnetic Resonance Spectrum (in CDCl ₃ ): Characteristic

Resonance peaks occurred at the following S (ppm; internal standard: TMS): 0.88 (d, 6H); 1.50-2.30 (m, 1H); 3.77 (s, 3H); 3.98 (d. 2H); 6.67 - 7.90 (m, .9H); 8.27 - 8.43 (m, 1H)
s = singlet; d = doublet; m = multiplet.

Example 6

2- (Ethoxycarbonyloxy) -5- (2 ·, 4'-difluorophenyl) benzoic acid, ester with 2-methoxyphenol (formula I with. _R β -C

The compound named in the title essentially became so prepared as indicated in Example 3: from 2-hydroxy-5- (2 ', 4'-difluorophenyl) benzoic acid, Ethyl chlorocarbonate and 2-methoxyphenol. After the usual washing, it froze Compound and was recrystallized from diisopropyl ether. Melting point 90 to 92 ° C;

Thin-layer chromatographic investigations as in Example 3 showed a uniform spot with R _f = 0.87.

Infrared spectrum (nujol): characteristic absorption bands

occurred at the following frequencies: 1760, 1740 cm " ¹ .

ο © οο

0 OO Q

e σ ο ο

3 1 4 B Λ: ^ 4

QUO

K © mmagnetJ8ch © s .Resoaanasffisktram CCDCI ^) § characteristic

Resoaan peaks occurred with the following c

(ppm ^ internal standard; TMS):

25 (3H _P t) j 3.75 (3H, s); 4.20 (2H, q); 53 - 7.77 (OT, m)? 8.13 - 8.23 (1H, m).

^c Siäglettf t = triplet; q = quartet;

Claims (15)

Dr. Ing. E. Uebau
Patent attorney (1835-1975) LIEBA ο oo eo «Β β O ITF Dipl. Ing. G. Liebau patent attorney Bitkensirasse 39 D-8900 Augsburg Patent attorney "Liebau & Liebau ■ Blrken straas" 39 · D-8900 Aupaburg Telephone (0821) 96096 cables: elpatent augsburg SELVI & C. S.p.A. Via Gallarate, Milan / Italy Your sign:
your / votro ref. S. 11450 Unaor characters:
our / notro ref. 7th Λ P.'V) PA date
to date Patent claims : , lj New 2-hydroxy-5- (2 ' _r 4'-difluorophenyl) benzoic acid derivatives according to the following general formula where R can be hydrogen or an oxycarbonyl radical d @ r formula II in which X is a straight or branched alkyl group with 1 to 6 carbon atoms, phenyl, benzyl, (C _5-7 ) CyCIo- ., 2, 2 _f 2-trichloroethyl or 2,2,2 ™ tribroniethyl. 2. A compound according to claim 1, characterized in that R Hydrogen, a straight or branched alkyl group having 1 to 4 carbon atoms or benzyl. 3. A compound according to claim 1, characterized in that it is 2-hydroxy-5- (2 *, 4'-difluorophenyl) benzoic acid, Ester with 2-methoxyphenol. 4. A compound according to claim 1, characterized in that it is 2- (benzyloxycarbonyloxy) -5- (2 ', 4'-difluorophenyl) -benzoic acid, ester with 2-methoxyphen oil. 5. A compound according to claim 1, characterized in that it is 2- (methoxycarbonyloxy) -5- <2 ', 4'-difluorophenylbenzoic acid, Ester with 2-methoxyphenol. 6. A compound according to claim 1, characterized in that it is 2- (isobutylcarbonyloxy) -5- (2 ', 4'-difluorophenyl) benzoic acid, ester with 2-methoxyphenol. 7. A compound according to claim L, characterized in that ea calibrate around 2-ethoxycarbonyloxy) -5- (2 ', 4'-difluorophenyl) benzoic acid, ester with 2-methoxyphenol; acts. 8. Process for preparing compounds of formula O Q 314 8 'Ί 2 4 -3 - wherein R is as defined addressed in 3., characterized gekennseichn © t "that a molar proportion of a compound of Fonsei III from about 2 to about 4 ". molar equivalent of a compound of Forsiel O Y-C-O-X IV wherein Y is a halogen atom and X is as defined in claim 1, b @ i at a temperature between about -10 ° C and about room temperature during, a period varying between about 10 minutes and about 40 ms, in an anhydrous organic solvent and reacted in the presence of a tertiary organic nitrogen-containing base _e so da.® is a compound of the formula results in the X wi © in with a low © »molar binding according to Forms1 III) 1 is defined, the (versus Ver-2-MQthosyphenol the formula at a temperature between about -10 ° C and about room temperature for about 3 to about 8 hours is implemented, the method also being characterized is that when X is 2,2,2-trichloroethyl or 2,2,2-Tribroraäthyl means the compound according to formula V a selective hydrogenolysis can undergo, so that the compound of formula I results in which R is hydrogen is. 9. A method for the production of compounds of claim defined type, with R - hydrogen, characterized in that a molar proportion of a compound of the formula .COOH III with about 3 to about 7 molar equivalents of 2-methoxyphenol the formula 5H VI in the presence of a catalytically effective amount of a strong acid in an inert atmosphere at the melting temperature of the reaction mixture is brought into contact. 10. Pharmaceutical approach with antipyretic, pain relieving, anti-inflammatory and expectorant. Own Shafts , as a result, as an active ingredient, it contains about 3SO bie © tw® 1700 mg of an egg compound according to claim 1, mixed with iron pharmaceutically acceptable medicament carriers, contains “ 11. Pharmaceutical Änsats according to claim 10, characterized in that that it contains at about .350 to about 1700 mg of a compound according to claim 2 as the active ingredient. 12. Use of the compounds according to claim 1 as ent- ' zündungshenuaenele, schmerslinäerung, fisbersenkende and ejection-promoting substances. 13. Use of the compounds aacsfo claim 2 as inflammation-yaffiffleiMä®, Schmerglinderade ^ fever-lowering and ejection-promoting substances. 14. Method sum treatment of warm-blooded animals, including humans, ä & characterized in that a desünöungshemaei & eä® Schnnerzlindernd ^ fever-lowering and expectorant Meag © eiaer compound according to claim 1 is administered. 15. The method a®ch spoke 14, characterized in that Effective Sfe & <g © awischon about 5 and about 25 mg / kg