DE1967205C2 - Use of substituted pyrazole-4-acetic acids - Google Patents

Description

and their salts with inorganic and organic bases in the fight against rheumatic and other inflammatory disease processes.

Formula I.

The invention relates to the use of substituted pyrazole-4-acetic acids of the general

R ⁴ R ² CH-COOH

I come from salt-forming pharmacologically acceptable mono- or polyvalent cations, for example Lithium, sodium, potassium, calcium, magnesium and aluminum or optionally also quaternary Ammonium ions from nitrogen bases, such as ammonia, ethanolamine, diethanolamine, triethanolamine, Ethylenediamine, glucosamine or N-methylglucosamine are possible.

The substituted pyrazole-4-acetic acids can according to the German Offenlegungsschrift DE-OS 19 46 370.8.

It has been found that substituted pyrazole-4-acetic acids of the general formula I and their salts, with low toxicity, pronounced antiphologistic, analgesic and have temperature-lowering effects and therefore in combating the most diverse rheumatic or other inflammatory disease processes can be used. the end some selected examples compiled in Tables 1 to 4 shows that the substituted pyrazole ^ acetic acids of the general Formula I and their salts, when used according to the invention, the listed comparative preparations due to their stronger anti-inflammatory or analgesic or, temperature-lowering effect and are superior due to their greater therapeutic range.

R ^{1 is} a phenyl group which can also have a substituent in the form of a methyl group, a halogen in the form of fluorine, chlorine and bromine, a methoxy or a trifluoromethyl group,

R ^{2 is} a hydrogen atom or a phenyl group, which can also carry one or two identical or different substituents in the form of a methyl group, a halogen in the form of fluorine, chlorine and bromine, a methoxy or trifluoromethyl group,

R ^{3 is} a hydrogen atom or a phenyl group, which can also carry a substituent in the form of a halogen as fluorine, chlorine and bromine, or a methoxy group, where R ² should not be hydrogen and R ³ hydrogen at the same time,

R * stands for a hydrogen atom or a methyl group,

and their salts with inorganic and organic bases in combating rheumatic and ω other inflammatory disease processes.

For example, the diseases to be treated are progressive rheumatic arthritis, rheumatic Fever, irritation in osteoarthritis, painful postoperative swellings and inflammations, joint effusions, Sprains etc, into consideration.

As salts of the substituted pyrazole'4'acetic acids of the general formula which can be used according to the invention

Table 1

R ¹

R ¹

LD ₅₀ Inhibition of Therap.QuoL mouse Carrageenin LD ₅₀ ZED ₄₀ mg / kg Edema i.p. by 40% (Rat)*) HD ₄₀ mg / kg orally

(Nicopyron ad Inj.) H.

800 MOOO

279

400

600

500

440

250

63

242 35

120 16

312

100

75 20

5.6

20.0

8.6

7.1

6.9

8 55.0

7.5

8.3

3.2

5.0

-125 100 -1.3

62.4

14.3

3.8

-80 > 6

= 80

continuation

LD ₅₀ Inhibition of Therap.Quot.

Mouse carrageenin-LD ₅₀ ZED ₄₀

mg / kg edema i.p. by 40%

(Rat)*)

ED ₄₀

mg / kg orally

> 125 <500

210 600 280

Mixture 250

> 125

144

CH ₃

ICO

199

340

55

75

-120

45

30th

> 2.3

-2.3

18 13.9

> 62.5

1

2.5

312 -120 -2.6

H
Ca-Saiz 770
orally 4th 193 H
Morpholine salt 215
ip 7th 30.7 H
N'methyl-
glucamine ^ salt > 1000
orally -20 > 50

continuation

R " LD ₅₀ 700 Inhibition of Therap.Qüot mouse orally Carragcniri- LD50 / ED4U mg / kg Edema i.p. 730 by 40% orally (Barrels) *) 830 Et) ₄₀ orally mg / kg orally H 25th 28 Ethylene diamine salt H -15 -Λ9 Piperazine salt H 10 83 Diethanol amine salt

*) Winter et al., Proc. Soc. ex |>; Biol. Med. 111, (1962) 544. Table 2

(Nicopyron ad Inj.)

H H H H H H

LDj ₀ inhibition Therap.Qüot mouse of the UV LD _5O / ED ₅ o mg / kg Erythema i.p. by 50% (Sea pig chen) *) ED ₅₀ mg / kg orally 800 > 300 £ 2.7 400 20th 20.0 600 20th 30.0 500 > 20 <25

242

440

63

24.2

31.4

10.5

250 -20 -12.5

312

100

104

0.3

continuation
R ¹

ίο

LDso inhibition Therap.Quot mouse of the UV LD _5o / EDso mg / kg Erythema Lp. by 50% (Sea pig chen) *) ED ₅₀ mg / kg orally

75

4.5 16.7

> 500

> 50

> 125 _? <500

> 10 (~ 20) <41.7

Cl

280

140

CH ₃ O

Mixture 250

125

CHjO-

ν / v

1.5

13.1

Cl-

Cl-

51

-51

199

39.8

Cl-

340

Na-SaIz

312

113.3

Cl

y v

H 215

Morpholine i.p. salt

71.7

*) Winder et al "Arch. Int. Pharmacodyn. 116 (1958) 261.

ii

12th

Table 3

(Nicopyron ad lnj.) Artiinophenazori

LD ₅₀
mouse
mg / kg
ip Analgesic
Effect*)
ED ₅₀
mg / kg po More therapeutic
quotient
LD ₅₀ / ED ₅₀ 800 250 5.3 330 50 6.6 400 > 60 <6.7 600 50 12th

250

18th

> 20

17th

-4.5

> 30

> 30

-12

17th

13.4 <6

14.7 -14

<8.3 156 <7 35

-21

18.4

*) Measured on the average delay in the defense reaction of the mouse by 40% during 2 hours at Irritation of the base of the tail with a focal ray.

Table 4

14th

LD ₅₀ mouse mg / kg ip

Anlipyf.

effect

Lower el. temp.

(Ralte)

around 1.5 ° C

ED ₁₁ J

mg / kg! .ρ »

Therap.

quotient

(Nicopyron ad Inj.)
Aminophenazone

800 300

279 242 250

280

> 300 70

<20> 20> 20

17th

2.7 4.7

<12.5

16.5

For use according to the invention, the substituted pyrazole-4-acetic acids of the general Formula I and its salts are produced or administered in the form of pharmaceutical preparations.

The pharmaceutical preparations can be oral, rectal or parenteral as solutions of salts, ζ. Β. intramuscularly or intravenously.

For oral use, the active ingredient can be made into tablets, granules, capsules, or drinkable syrups

L f

sterile, especially isotonic solutions ίη question come.

As an example of the production of a pharmaceutical preparation in the invention Can be used, the following recipe is described:

Ännan with

be provided with a coating resistant to gastric acid. Tablets can be conventional carriers such as Lactose, sucrose, corn or potato starch, amylopectin, Gelatin, ethyl cellulose, gum arabic, talc and lubricants such as magnesium or calcium itearate or polyethylene glycol. For rectal use, suppositories can be formulated Are, while for parenteral administration, formulation for tablets

Contains tablet

mg of I3.5-triphenyl-pyrazoi-4-acetic acid mg corn starch mg lactose mg magnesium stearate

The finely ground and sieved active ingredient is mixed with the other ingredients and made into tablets pressed

Claims (1)

Claim; Use of substituted pyrazole-4-acetic acids of the general formula I. CH-COOH worm 15th R ^{1 is} a phenyl group which can also have a substituent in the form of a methyl group, a halogen in the form of fluorine, chlorine and bromine, a methoxy or a trifluoromethyl group, R ^{2 is} a hydrogen atom or a phenyl group, which can also carry one or two identical or different substituents in the form of a methyl group, a halogen in the form of fluorine, chlorine and bromine, a methoxy or trifluoromethyl group. R ^{3 is} a hydrogen atom or a phenyl group, which can also carry a substituent in the form of a halogen as fluorine, chlorine and Br-n, or a methoxy group, where R ² should not be hydrogen and R ³ hydrogen at the same time, R ^{4 represents} a hydrogen atom or methyl group,