DE2243305C3 - New derivatives of phenylacetic acid, processes for their production and pharmaceutical preparations containing the derivatives as an active ingredient - Google Patents

Description

—C— or —C-

Il ο

OH H

is, R, R ₂ . R ₃ and R ₄ , which can be the same or different, each represent hydrogen atoms or methyl residues, but only one of the radicals R ₂ , to Rj and R _{4 is} methyl, and represents a single bond or a C =C double bond, and their pharmacologically harmless salts with inorganic and organic bases.

2. Process for the preparation of compounds according to claim I, characterized in that one in a manner known per se

a) Compounds of the general formula

R ₂ -CH ₁ CO

CH - COOR '

(D

in which R and R _{2 have} the meanings given above and R 'is a hydrogen atom or a lower alkyl radical, is reacted with formaldehyde or a formaldehyde polymer and a hydrochloride of a secondary amine in an alcoholic medium,

b) the amino ester obtained in the presence of an alkali metal alcoholate with an alkyl sulfate and a ketoester of the general formula

R ₄ -CH ₂ -CO-CH-COO alk

R ₃

45

in which R ₃ and R _{4 have} the abovementioned meanings and alk is a lower alkyl radical, to form an ester of the general formula

cDdißseS.'iuregeit in (better known Way with alkali borohydride or aluminum isopropylate in isopropanol at boiling point to give the compound of the general formula

R ₁ - <^ Z) - cn coon

OH R ₄ ^R 'V)

reduced and if necessary

e) the above keto or hydroxyl compound in a manner known per se in the presence of palladium or platinum oxide catalytically to a compound of the general formula

OH R ₄

> -CH COOH

(VII)

hydrogenated and optionally

f) the compound of the general formula VIl in a manner known per se with the aid of an alkali metal dichromate in acidic medium to a compound of the general formula

(VII!)

oxidized and, if desired, the compound obtained in its pharmacological manner in the usual way transferred harmless salts with inorganic or organic bases.

3, pharmaceutical preparations, especially with anti-inflammatory and analgesic Properties, characterized by a content of a compound according to claim 1 as an active ingredient and on a therapeutically safe carrier.

—CH-COO alk

(IV)

55 The invention relates to novel derivatives of phenylacetic acid, which have interesting and valuable pharmacological properties, a process for their preparation and pharmaceutical preparations containing the derivatives as active ingredients.

The new derivatives according to the invention have the formula

implements,

c) the ester of the general formula IV in a manner known per se to the corresponding acid the general formula

R., - ^ C // - ^ > -CH COOH

R ₃ -

60 ><f> - CH-COOH

Y ^ = / ι

R, ^R

in which A is a group of the formula

(X)

OR ₄

(V)

c-

or

/ \
OH H

saponified.

is R. R ₂ , R ₃ and R ₄ , which may be the same or different

22nd

may stand for Wasscrstoffatome or Mcihylresic each, but only one is R _2, R ₁ and R ₄ Melhyl, and - is a single bond or a C - ■ represents C double bond, and their pharmakologisi; h acceptable salts with inorganic and organic Bases.

The invention is also directed to the preparation of the derivatives of the formula X by a process which is characterized by it. that one in a known manner

a) Compounds of the general formula

R, - C ¹ H ₂ CO

> CH COOR '

(I)

in which R and R _{2 have} the abovementioned meanings and R 'is a hydrogen atom or a lower alkyl radical with formaldehyde or a formaldehyde polymer and a hydrochloride of a secondary amine in an alcoholic medium.

b) the amino ester obtained in the presence of an alkali metal alcoholate with an alkyl sulfate and a Ketoesler's general formula

R ₄ -CH ₂ -CO CH -COO alk

in which R ₃ and R _{4 have} the abovementioned meanings and alk is a lower alkyl resl, to form an ester of the general formula

R ₃ - <J ^ y> - ^^^ - CH-COO alk

O R,

(IV)

implements,

c) the ester of the general formula IV in a manner known per se to the corresponding acid of the general formula

OR ₄

CH - COOH

(V)

saponified,

d) this acid, if appropriate in a manner known per se, with alkali borohydride or aluminum isopropylate in isopropanol at the boiling point to give the compound of the general formula

305

e) the protruding keto or hydroxyl compound in a manner known per se in opposition to palladium or Pluiinoxyd catalytically to a compound the general formula

CH-COOH

i
R.

(VII)

hydrogenated and optionally

O the compound of the general formula VII in a manner known per se with the aid of an alkali metal dichromate in acidic medium to a compound of the general formula

OR ₄

> CW COOII

^x I

(VIII)

^Ri

cn cooii

OH R ₄
reduced and if necessary

(Vl)

oxidized and, if desired, the compound obtained in its pharmacological manner in the usual way transferred harmless salts with inorganic or organic bases.

The process according to the invention for the preparation of the compounds of formula X particularly comprises as an example in FIG. I a and! sequence of reactions shown in b.

In Reai'tion A with the starting derivatives of the formula i, in which R 'is a hydrogen atom or a Is an alkyl radical (especially an ethyl radical). formaldehyde or a formaldehyde polymer (trioxymethylene) and a hydrochloride of a secondary amine, e.g. B. Piperidine, dimethylamine or morpholine, in an alcohol (especially ethanol) at the boiling point implemented by the method described in Organic Reactions, Vol. 1, p. 329. In the formula of the amine, R "and R" 'each represent an alkyl radical, or they form a heterocycle together with the nitrogen atom to which they are attached. which may contain another heteroatom. The reaction can also be carried out in acetic acid.

If an acid (R '■ = H) is assumed, this acid is esterified during the reaction at the expense of the alcohol used as solvent. In all cases, the ester of the formula !! obtained in the form of the hydrochloride. The raw product is used as such for the further reaction sequence. The compounds of the formula I used as starting materials have been described by D. Papa and co-workers (J. Amer. Chem. Soc. 1946, 68.2133) for the case where R = R ₂ = H and R '"M or C ₂ H ₅ . They are obtained here by acylation of ethyl acetate, optionally with subsequent saponification of the ester In the same way, the derivatives of the formula I in which R is a methyl radical, R _{2 is} a hydrogen atom or a methyl radical and R 'is a hydrogen atom or C ₂ H ₅ is, by acylation of a phenylacetic acid or a phenylacetic acid ester, which is optionally methylated in the "position.

Reactions B and C are carried out in a single operation. The compound of the formula III formed as an intermediate is not isolated here. In practice, the crude ester of formula II is dissolved in ethanol containing I equivalent of sodium ethylate, dissolved at low temperature (5 to +5 C) with an ethanolic solution of acetoacetic ester (R, = R ₄ = H) or a homologous one Treated ketoesters (R ₃ or R ₄ = methyl) and converted into the sodium derivative with a second equivalent of sodium ethylate. Methyl sulfate is added to the mixture at low temperature, whereupon the lister of the formula V is isolated by conventional methods.

During reaction D, the lister of formula IV is saponified by treating it with an alkali metal carbonate in solution in aqueous alcohol is brought to the boil. The acids of the formula V are acidified isolated and purified by crystallization or distillation. This reaction D can also be used in the Cold carried out with sodium hydroxide or potassium hydroxide dissolved in aqueous alcohol will.

The kelo acids of the formula V can with an alkali boroh> drid. that in water or aqueous alcohol is resolved. or with aluminum isopropylate the boiling point in isopropanol under the usual conditions of the Meerwcin-Pondorf reaction (Org. Reactions. Vol. 11, p. 178) / u Hydroxylderivatcn der Formula VI can be reduced (reaction E).

The acids of the formula VII are replaced by catalylic Obtained hydrogenation of the acids of formula VI in the presence of palladium or platinum oxide (Reaction Fi. You can also directly from the acids of the formula V by catalytic hydrogenation dei double bond and simultaneous reduction of the group CO produced in the presence of platinum oxide "earth

The acids of formula Viii are made from acids the I-ormel VlI by oxidation of the OH group / around ketone with the help of an alkali dichromate in one siuiicii medium prepared (reaction G).

The dermal of the formulas V. VI. VII and VIII are the Dem.nc «email of the invention, all under the "ibeni'i'ii.innie general formula X fall.

U e i s ρ ι c I I

4i <<) "o I Lvclohexyl-phenyl-acetic acid
Il ormirl VRR ₂ R, R ₄ H)

Λ 54 g (0.2% mol) of 4-acctylphenylacetic acid alcohols (formula I: R "- · R ₂ H; R 'C ₂ H ₅ ) are mixed with 31 g (0.26 mol) of piperidine hydrochloride in 75 ml of ethanol (0.33 mol) trioxymethylene and a few drops of concentrated hydrochloric acid are dissolved.The solution is brought to the boil for 1 hour and then after another addition of VI, r trioxymethylcn (7.2 g) for a further 2 hours The residue consisting of the hydrochloric acid of the isher of the formula II is used as such for the sequence of reactions (weight 59 g; 0.174 mol; yield 67%).

BC / u of a solution of sodium ethylal. Prepared from 2.7 g (0.117 gAtom) sodium in 65 ml Älh.mol 18.5 ml (19 g, 0.14 mol) acetoacetic acid.ilhylcsicr and then at 5 C 16 g (0.047 mol) of the hydrochloride of the ester of the formula II (R = R ₂ = H) given. While the mixture is kept at 3 ° C. by cooling, 10.7 ml (0.11 mol) of methyl sulfate are added dropwise over 45 minutes, followed by stirring at room temperature for 18 hours. The alcohol is evaporated and the residue is taken up in water and extracted with ether. After evaporation of the ether, an oily residue remains, which consists of the ester of the formula IV

ro (R = R ₂ · = R, = R ₄ = H).

D. The ester of the formula IV obtained in the manner described is kept at the boiling point t for 24 hours with HOmI of an aqueous 10% strength sodium carbonate solution and 40 ml of ethanol. The alcohol is then evaporated off and the aqueous solution washed with ether and acidified, with 9 g of acid of the formula V (R - ■ = R ₂ = R ₃ ~ R ₄ - H) being precipitated. Melting point 125 C. bulge 85%.

Elemental analysis for Ci ₄ H ₁₄ O ₃ :

Calculated ... C 73.02. H 6.13%: found .... C 72.8, H 6.4%.

B e i s ρ i e I 2

2- [4- (3'-Oxo-l'-cyi-lohcxenyl) -phcriyl] -propionic acid (Formula V: R ------ C ¹ H ,; R ₂ R, - R ₄ - H)

A. This step is carried out in the manner described in Example I, starting from 10 g (0.052 mol) of 2- (4-acetyl-phenyl) propionic acid (formula: R = CH,: R ₂ - = H; R ' - ^: ~ - H ). Piperidine hydrochloride and trioxymethylene carried out in ethanol at the boiling point.

When the reaction is complete, the hydrochloride of the corresponding ester of the formula II The cost of the ethanol used as a solvent, isolated.

B. C. These steps are carried out as in Example 1

Umsel / ung of the hydrochloride of the ester of the formula 11 (R-CH ,; R ₂ = H) with the sodium derivative of acetoacetic acid ester in the presence of an excess of sodium ethylate and methyl sulfate carried out with cooling to 5 C and then at room temperature.

The ester of the formula IV (R = CH ₃ ; R ₂ = R_, = R ₄ = H) is isolated in the customary manner.

D. The ester of the formula IV obtained in the manner described is modified to that described in Example I. Way with sodium carbonate in aqueous alcohol

saponified. The acid is obtained in the form of an oil which crystallizes by trituration with isopropyl oxide, Weight 5 g. Melting point I27 "C. Overall yield 40%.

Elemental analysis for C ₁₅ H ₁₆ O ₃ ; Calculated ... C 73.75, II 6.60%; found .... C 73.45, H 6.35%.

Example 3

4- (3'-Hydroxy-r-cyclohexenyl) phenylacetic acid (Formula VI: R = R ₂ = R ₃ = R ₄ = H)

0.5 g (2.17MoI) of the acid of the formula V described in Example I are in 10 ml of water in the form of the sodium salt dissolved by adding sodium hydroxide. Be under within an hour Stir at 5 "C, 0.4 g (10.6MoI) of sodium borohydride

added. After stirring for another hour and Acidification with HCl, the precipitate is filtered off, washed, dried and washed with chloroform. Weight 0.2 g (40%). Melting point 148 "C.

Elemental analysis for C ₁₄ H ,,, O ₃ :
Calculated ... C 72.39, H 6.94%;
found .... C 72.15, H 7.30%.

The same product can also be made as follows: ι ο

2.3 g (10 mmol) of the acid of the formula V described in Example 1 are dissolved in 20 ml of isopropanol which contains 4 g (20 mmol) of aluminum isopropoxide. The mixture is refluxed while removing the acetone formed in the reaction. This removal is continued by reacting the distillate with dinitrophenylhydrazine (reaction time 1.75 hours). The alcohol is evaporated off under reduced pressure, the residue is acidified with 1N HCl and the insolubles are filtered off, purified by conversion into the sodium salt with NaHCO ₃ and acidification again and finally by washing with chloroform. Weight 1.1 g (50%). Melting point 140 C.

Be i s ρ i e I 4

4 - (. V-HydroxycyclohexyI) -phenylacetic acid c
[Formula VII: R - R ₂ = - · R ₃ = R ₄ = H)

2 described in Example 3 g acid of formula VI are dissolved in 30 ml of ethanol and hydrogenated under normal pressure at room temperature in the presence of 0.2 $ of 5% palladium carbon. After the theoretical amount of hydrogen has been taken up and the catalyst has been filtered off, the alcohol is evaporated off and the residue is crystallized from chloroform. Weight 1.5 g (75%). Melting point 173 C.

Elementary analysis for Ci ₄ H ₁₈ O ₃ :
Calculated ... C 71.77. H 7.74%;
found .... C 71.50. H 7.65%.

The same product can be obtained by hydrogenating the acid of the formula V described in Example 1 in Ethanol can be produced in the presence of platinum oxide

Example 5

4- (3'-oxocyclohexyl) phenylacetic acid c
(Formula VIII: R - R ₂ == R., = R ₄ "-" Hl

To 0.5 g of the acid of the formula VII described in Example 4 in 5 ml of ether, between 0 and 5 ° C 1.5 ml of a chromic acid solution cooled to 0 "C. (made from 9.7 g of potassium dichromal, 30 ml Water, 7.4 ml concentrated sulfuric acid, made up to a volume of 50 ml). After a stirring period A further 1.5 ml of chromic acid are added after a few minutes. The mixture is stirred for 5 minutes and the aqueous phase is decanted and extracted with ether. The ether is washed with water, dried and evaporated. The oily residue is distilled under reduced pressure. Weight 0.5 g (100%). The product is crystallized from cyclohexane. Melting point 96 C.

65 Basic analysis for C _K H _lf , O ₃ :

Calculated ... C 72.39. H 6.94%
rounded ... C 72.23. H 6, K 2%.

Example 6

2- [4- (3'-Hydroxy-r-cyclohexenyl) phenyl] propionic acid

(Formula VI: R = CFI ₃ ; R ₂ = R ₃ = R ₄ = H)

This acid is obtained from the acid of the formula V described in Example 2 by reduction with sodium borohydride in the manner described in Example 3. The acid is crystallized from ethyl acetate. Yield 80%. Melting point 142 ⁰ C.
Elemental analysis for C ₁₅ H ₁₈ O ₃ :

Calculated ... C 73.15, H 7.37%;

found .... C 73.25, H 7.28%. .

Example 7

2- [4- (3'-Hydroxycyclohexyl) phenyl] propionic acid
(Formula VII: R = CH ₃ ; R ₂ = R ₃ = R ₄ = H)

2.44 g (10 mmol) of the derivative of the formula V described in Example 2 are poured through in 30 ml of water Addition of sodium hydroxide dissolved up to pH 6 and then at room temperature under normal pressure hydrogenated in the presence of 0.5 g of 5% palladium carbon. After 3 hours is the theoretical amount of hydrogen been recorded. The solution is filtered and acidified. The oily precipitation is with Bred 30 ml of cyclohexane to the boil. The cyclohexane is decanted during the boiling. That as Remaining oil is dissolved in isopropyl oxide, then in benzene and finally in dichloroethane crystallized. Yield 30%. Melting point 133 to 143 C (mixture of cis and trans isomers).

Elemental analysis for C ₁₅ H ₂₀ O ₃ :
Calculated ... C 72.55, H 8.12%;
found .... C 72.56, H 8.31%.

The same product is obtained in a yield of 87% by hydrogenation of the derivative of the formula V described in Example 2 in an aqueous solution of the sodium salt in the presence of PtO ₂ or in solution in ethanol or methanol with PtO ₂ as the catalyst.

Example 8

2- [4- (3'-Oxocyclohexyl) phenyl] propionic acid
(Formula VIII: R = CH ₃ : R ₂ = R ₃ = R ₄ = H)

This acid is obtained by oxidation of the acid of the formula VII described in Example 7 in the manner described in Example 5. The crude product is converted into the semicarbazone and then regenerated by hydrolysis with 5N HCl for 2 hours. The product is crystallized from cyclohexane. Yield 56%. Melting point (closed tube) 88 to 90 ⁰ C

Elemental analysis for C ₁₅ Hi ₈ O ₃ :

Calculated ... C 73.15, H 7.37%;
found .... C 73.0, H 7.60%.

Example 9

4- (2'-methyl-3'-oxo-1'-cyclohexenyl) phenylacetic acid

(Formula V: R = R ₂ = R ₃ = H; R ₄ = CH ₃ )

A. This step is carried out in the manner described in Example I.

60961721C)

B.-C. 11 g (0.076 mol) ethyl propionylacetate are converted into the sodium derivative with sodium ethylate in 500 ml of ethanol. Be at 5 ° C 26 g (0.076 mol) of the ester of the formula II described in Example 1 (stage A) and then 16 ml of methyl sulfate added. After one hour at 5 ° C and then after 20 hours at room temperature, the ethanol, evaporated and the residue taken up in water and, ether. The ether phase and the washing liquids are combined, washed at ρH value 5 and then concentrated. The ester of formula IV will arise in the form of an oily residue.

D. This oil is saponified by keeping it at the boiling point with 110 ml of an 10% strength aqueous Na ₂ CO ₃ solution and 40 ml of ethanol. After the ethanol has evaporated, redissolved in water and decolorization with activated charcoal, the acid is precipitated by acidification and then purified by conversion into the sodium salt, which is washed with methanol and then with ethanol. Acidification gives the acid which crystallizes in ethyl acetate. Yield 10%. Melting point 126 ° C.

Evaporation of the ethanol and filtration is obtained by acidification of an oily acid, which with ethyl acetate is extracted. Evaporation of the solvent leaves a residue, which is in a

A ^{and C} , ^{water and} methanol crystallized. Yield 33%. Melting point 124 to 125 ° C.

Elemental analysis for C ₁₆ H _n , O ₃ :

Calculated ... C 74.39, H 7.02% · _Io found ... C 74.39. H 7.24%.

Example 12

'5 2- [4-16'-methyl-3'-oxo-1' -cyclohexenyD-phenyl] propionic acid

(Formula V: R ₃ = R ₄ = H; R = R ₂

0 107

Elementary analysis for Ci ₅ H ₁₆ O ₃ :
Calculated ... C 73.75, H 6.60%; found .... C 73.93, H 6.80%.

Example 10

4- (4'-methyl-3'-oxo-l'-cyclohexenyl) phenylacetic acid

(Formula V: R = R ₂ = R ₄ = H; R ₃ = CH ₃ )

A. This step is carried out in the manner described in Example 1.

B.-C. 11 g (0.076 mole) of methyl acetyl acetic acid are treated in the manner described in Example 9 and converted into the ester of formula IV, which is obtained in the form of an oil.

D. The oil is saponified in the manner described in Example 9. The raw obtained by acidification Acid is crystallized from ethyl acetate. Yield 50%. Melting point 134 C.

Elemental analysis for C ₁₅ H, _ft O ₃ :
Calculated ... C 73.75, H 6.60%; found .... C 73.50, H 6.48%.

^{Mol) 2} - ^<4 -P "-opiony] _P -phenyl) -propionn ^We \ g ^{to 50 ml in} acetic acid with 12.9, P ^{Pl eridlnh} ^ rochlorid. 4.8 g (0.16MoI) ' ^{en and} ° ·' ^{ml of} concentrated HCl dissolved. T? ^{at 90 "C, the} acetic acid ^is off ^{and d} rf ^Residues * nd in water and ether ^mm - ^{n, le Wäßri} S ^{e phase} is separated, ether we ^{m ad} V ^nd extracted ^{with ether} The ätherkl, ^{U?.." he K} * ^C0 > g ^etro <* net and with a, o DaSHvH Ji ⁰⁸ V !? ⁸ mixed with anhydrous HCI. Si ^{l0nd of the ester of the formula} » ^{is in}

^{32g i8!%) From} g ^enutsc ht- Schmelzty ^ hlorid of the ester of the formula II des nÜ ^} T ' ^{rd In an} ethanolic solution W218 ST? ^the Acetessigsäureäthylesters • i _"f ^ei u ^{gef? hrt and} methyl sulfate to the Ä * ~ ^{s. Beis} P ^hank manner described

ih n <, ^R f ^KÜ r ^{is ended by} allowing it to ^stand for ^{4 Ϊ 17 hours at} 2OX and heating the raw it ί " ³ ^ ^reflux condenser. The aSI Γ ^γ · ^ΟΠΓ - ^ίίν is evaporated

S Ä1? ^aktiOn ™ ^{Äth d Wi}

The
will

Example 11

2- [4- (2'-methyl-3'-oxo-r-cyclohexenyl) -phenynpropionic acid

(Formula V: R = R ₄ = CH ₃ ; R ₂ = R ₃ = _H)

A. This step is carried out in the manner described in Example 2. ocstnne-

B.-C. 31.5 g (0.21 mol) Propionylessigsäureäthvlester are converted with sodium ethylate into the sodium derivative and condensed with 30.2 g (0.085 mol αϊ m Example 2 described ester of the formula Π. After the usual work-up, the ester of formula IV in form of a DIs erhaUen D the crude ester is saponified by being held with 150 ml IOW aqueous Na ₂ CO ₃ solution and 60 ml Ä Hano at the boiling point. According to the ^{ester of formula IV} is treated with a

T "^ ^CO > - ^Lösm Z saponified in the manner described ^{in the B} ^ ^ls P ^iels.

Γ ^Ansauer "ng of the sodium salt ^d ^ ^with ethyl acetate and Isopropyi-SuniovvJ ^andby chromatography on Alu-KTm ^y ι. ⁸ """" ⁸¹ · ^Here, 7g (26%) TS, ^{Pr d?, UKTs erhaIten 'which} is characterized by its X ^ u ^«ltraviole" spectra. Gew, chtO5R ^for r ^C' i ^HL8 ° ³ flattened molecular SSι V? Κ ■ ' f ^Unden i ^acid imetrisch): 260.

duSshemi ^ln i ^Unge ! l ^{the F} ° ™ elX have inflammation of the ThT ^{nde u} . ^nd / "algesic properties that heumatSh K ^lnsbesond ere for the treatment of ^diseases SKSM r i ^r Rheumatoid arthritis, local Fn. ¹ J" ^{1 "5 'S} P ^ond ylarthritis etc.) and i EiLn ir ^SSE" can be ^{enut2t from} S . eh ⁸ ^? ^aft u ^"be demonstrated in particular by the T ^{c be} f hnebenen classical pharmakoloainVT ^he.

an I «/ ^, r ^{Or8called by} subcutaneous injection of H? ntenÄ ^Carra S ^{ecni n '} solution into the sole of one of 7ht.n ^rRaUe · ^{The animals} are in groups ° yil' Τ? ¹ ' ^{And kept at 2TC} The oral saline solution is given.

<Γ

Per
duct
from
at
game DA ₄₁ ,
(40 "/" iger
Schulz)
against that
ΓίΐΓπι-
gecnin-tMcm IN THE,,,
(5 <>% igcr
Schulz)
against
UV light Schulz against
the dcnaturic
tion of
Proteins IM ₅₀
Analgesic (mj! kg onil) (HiJ! Kg oral) (mg kg oral) 1 70 5 25th 2 1 0.7 4 4
(= Phenyl
butazon) 4th 15th 4th + 4 25th 5 15th 4 + 7th 0.3 0.5 f 4 9 25th 1.5 4 4 30th 10 20th 11th 2 1.2 4 4

The treated animals receive the animal to be examined orally Substance 1 hour before the injection of the carragcenin. The animals are 3 hours after the Education of the edema killed. Protection against the edema is provided by comparing the volume of the Hind paws of the comparison animals and the treated animals were determined.

b) Erythema caused by ultraviolet radiation in guinea pigs, their lateral dorsal zone has previously been freed from hair. The irradiation takes place with a mercury vapor lamp of 500 W for 2 minutes from a distance of 18 cm 1 hour after the administration of the test Product. The protection against erythema is substantial and is based on an arbitrary Bc rating scale expressed from 0 to + 4- +.

c) Protection against the denaturation of proteins in vitro (see M i ζ u s h i m a. Arch. Int. Pharmaco. 1964 - 149 I to 7 and 1965 157 115 124).

d) Analgesia test by K ο s t e r (Feder. Proceed. 1959 - 18 - 412) by determining the protective effect of the investigated products against the Pain caused in the mouse by intraperitoneal injection of acetic acid.

The results are summarized in the following table:

known isomers of the formulas

HO

/ "V-CH-COOH

(D

en — Coon

CH ₃
CH-COOH

CHj

35

45

The products of formula I have a low toxicity. The lethal dose in the rat is im Average 100 to 500 mg / kg orally. The products have no effect on the central nervous system.

The anti-inflammatory effect of compounds of Examples 7 and 8 of FIG present application with the formulas

OH

CH ₁

55

60

/ V-CH-COOH

(2)

The anti-inflammatory properties were determined with the help of classical pharmacological experiments carried out, once the edema of the hind paws caused by carrageenin of rats and, on the other hand, of the erythema caused by ultraviolet radiation in guinea pigs, after administration of the compounds.

The edema on the paw is detected 2 to 3 hours after the injection of the carrageenin by plethysmography determined. The results are expressed as the percentage of mean inhibition and effective The dose at which there is 40% protection against the edema becomes just like the statistical significance determined by the ratio to comparison animals (student's test).

4 = ρ < 0.05.
4 4 = ρ <ο, ΟΙ.

4 4 4 = ρ < 0.001.

The determination of the erythema caused by UV light in guinea pigs is carried out in a blind test on three erythematous zones per animal with a rating of 0 to 3 and therefore one Maximum rating of 9 carried out.

The dose that prevents 50% (DA ₅₀ ) of the erythema, like the statistical significance, is carried out according to the test by Mann and W hi 11 η ey.

The results are given in the table below:

40

Verbin- 40% iger Schulz against the

dunucn Carragccnin-tJdcm. I) A _4n O

No. mg / kg

1 0.3 mg / kg 4 4

2 0.5 mg / kg 4 4

3 IO mg / kg 44+

4 3 mg / kg f 4 4

OK% Schulz
against UV-brylhem. DA ,,, oral, mg kg

0.5 mg / kg
0.6 mg / kg
5 mg / kg
10 mg / kg

with their corresponding, from DT-OS 19 49 987 These results show that the compounds 1 and 2 in the two tests carried out to determine the anti-inflammatory effect have 6 to 30 times greater activity than compounds 3 and 4.

All four compounds have a low acute toxicity (greater than 100 mg / kg) in the mouse and oral in the rat.

It follows that the compounds of the invention No. I and 2 have a very much higher anti-inflammatory properties Have an effect and a greater safety margin compared to the comparison compounds with regard to the acute toxicity.

The compounds according to the invention are also more effective than the known 4- (l-cyclohexcnyl) -phynylpropionic acid, as the following experiments show:

For compounds of the cyclohexyl phcnylpropionic acid type, the range of DA values is ₅₀ or

Ι) Λ _41; / wipe the known compounds and the compounds according to the invention in absolute terms very resentful, since they were given in low doses at which all compounds show their effectiveness. The compounds according to Examples 2, 6, 7 and S are clearly more anti-inflammatory than the known 4-M - cyclohexenyl) phenylpropionic acid. especially in carrageenin edema. Incidentally, the tendency is the same for the other anti-inflammatory tests.

In addition, the ratios between the DA ₄₀ values calculated in the carrageenin oem test and the doses at which the first signs of ulcer formation appear (which gives a margin of safety rating) are for the compounds of the present invention more advantageous.

IM ₄₁₁

4- (1-cycluhexenylJ-phenylpropionic acid
(known)

4- (1-Cyclohexenylj-phenylpropionic acid
(known) Example 2

4-ll-Cvcli) hexenyl) phenylpropionic acid
(known) Example 6

4- (1-cyclohexenyl) phenylpropionic acid
(known) example! 11th

4- (1- ('ytlohexenyl) phenylpropionic acid
(known) Example 7

4- (1-cyclohexenyl-phenylpropionic acid
(known) Example 8

Oirniyecnin-CJdcm

1.6

»1.8

The unsaturated compounds are just as active as the saturated compounds.

The methyl derivatives of Examples 11 and 12 are a a little less active, but also clearly less ulcerogenic and therefore also of the known compound consider from this point of view.

In the case of the compounds of the cyclohexylphenylacetic acid type the compounds according to the present invention (Examples 1.3 and 4) are also better effective as the well-known 4- (l-CyJohexenyl) -phenylacetic acid:

Connection # emflß example

4- (I '-CyclohexenyO-phenyl-

acetic acid (known)

<10% ίμ (.τ 5I) ¹ VOiJjCi * School / School / (! cjicn gcycn diis UV Ciirrii- Erylhem gecnin- DA ₅₀ ο ml ödcm init / kg THERE.,,,. (2 SUI.) onil (3 SId.) 20th 5 15th 5 14th 4th 30th 5

Although the derivatives have the Cyclohexylphenylpropionsäure in ι '! Common a stronger anti-inflammatory effect than the derivatives of phenylacetic acid, however, the derivatives show of phenylacetic acid sometimes greater analgesic effects.

The invention also includes pharmaceutical preparations. the one compound of the formula X or its pharmaceutically acceptable salt and one contain therapeutically safe carriers.

The preparations according to the invention can be administered as follows:

a) orally in the form of tablets, capsules or in any other pharmaceutically acceptable form Form with usual auxiliaries, the active ingredient in particular; in the form of Acid of formula X is present. The dose to be administered is on average 10 to 500 mg of active ingredient per day;

b) in the form of suppositories in average daily doses of 10 to 500 mg of the active ingredient;

c) in the form of injection solutions in a daily dose of 2 to 200 mg of the active ingredient, in particular in the form of water-soluble salts with alkaline or organic non-toxic bases can be obtained.

The dosage units of the preparations can be 1 to 250 mg of the active ingredient depending on the pharmaceutical Preparation and the method of administration to be used.

35

40

45

For this 2 Blaff; drawings

Claims (1)

Claims: 1. Compounds of the general formula COOH (X) IO in which A is a group of the formula