DE2003481A1 - Indazole derivatives with anti-inflammatory and analgesic effects - Google Patents

Description

DR. ING. A. VAN DER WERTH DR. FRANZ LEDERER

21 HAMBURG 90 8 MUNICH 80

W1LSTORFER STR. S3 - TEt. (0411) 770861 lUCILE-CRAHN-STR. 22 -TEL. (0811) 440846

Munich, January 27, 1970 L / W / BU

Applicant: ITALFARMACO S.p.A., Viale F. Testi 33, Malland Italy

Indazole derivatives with anti-inflammatory and analgesic effect

The present invention relates to a group of indazole derivatives with anti-inflammatory and analgesic effects In association with a very low Tox1z1tXt »soft for therapeutic purposes are useful.

The compounds of the present invention have the following general principles Formula (I) on:

(D i

00C ₄ H ₉

where R is an alkyl group with 1 bit 4 carbon or • Fomel troops

00983171936 ">.

BATH ORIGINAL

■ z-

(CH ₂ ) _n - N

means in which η represents an integer of 2 to 4, and where R "and R ^{H> can be the} same or different and AHyl groups each having 1 to 4 carbon atoms or together with the nitrogen atom can represent a perd1n group, a morpholine group or a piperazine group , while R * denotes a hydrogen atom, a halogen atom or an alkyl or alkoxy group having 1 to 4 carbon atoms.

Oils according to the invention can be prepared according to known Process starting from the sodium salt of the corresponding 3-hydroxyindazo1 of the general formula (II)

OH

CII)

GOOC ₄ H ₉

where R * has the meaning given above. by alkylation "It is an" AUyI halide dor formula

HoI-R,

009831/1935

BUILDING

-3 «
R has the meaning given above

e (Π) Minnen suisgshand mm the corresponding H-f4- € aHiobufc © 5f.ypheRy t} -an thrani 1 sKure dar-eh

?,? p. * 5 «-.yciizing RedufitiOtU?,. B. RiH zinc

getting produced"

Ee zinu already known IndazoldeHvtts old effect _? which of those dec ¥ © fllegenden general formula I by the presence of ^ © n substituents such as halogen THfluormethyl ·, alkoxy 1n the sn 1n Imposition the nitrogen atom bonded benzene ring are different. Compared with these known compounds, the compounds according to the invention have an increased anti-inflammatory and analgesic effect and a lower toxicity.

With the compounds of general formula (I) were carried out the following examinations:

a) Acute toxicity in rats orally

b) anti-inflammatory effects (edema of carrageenin)

c) analgesic effect (Randall-Seiltto method)

d) Investigation of behavioral catfish in mice.

a) Acute Toxi7.1t8t

The acute Toxtzita't was with white rats of the breeding variety Nistar examined orally. All substances were in the form of a 5% gum arabic suspension administered. The applied Doses ranged from 1 g / kg to 600 mg / kg. Within 24 hours there was no death. The animals behaved normally.

00 9831/193 5 ORIGINAL BATHROOM

b) Anti-inflammatory effect

The anti-inflammatory effect was determined with the aid of the differential volume meter from Basile, Malland. The edema was obtained by an intraplantar injection of 0.1 ml of a 1 t
Caused carrageenin lysis. As standard substances
Phenylbutazone and mefenamic acid (mephenamic acid) were used. All substances to be examined were administered orally one hour before the carrageenin treatment.

Measurements were taken at intervals of 1, 2, 3, and 4 hours after the carrageenin injection. The percentage protection values for the various
tested substances indicated:

ITF-631 100 mg / kg oral protection 3.00 % after 1 hour

61.20 % after 2 hours

(1- (4-Carbobutoxyphenyl) -3- (N, N- 54.60 % after 3 hours d1methylaminoa'thoxy) -1ndazoi) 55.40 % after 4 hours

ITF-632 100 mg / kg oral protection 23.50 % after 1 hour

71.00 % after 2 hours

(1- (4-Carbobutoxyphenyl) ~ 3- (ß- 44.00 % after 3 hours piperidinoethoxy-indazole) 37.80 % after 4 hours

ITF-634 100 mg / kg oral protection 95.43 % after 1 hour

39.45 % after 2 hours

(1- (4-Carbobutoxyphenyl) -3- (N, N- 43.70 % after 3 hours d18thy1am1noethoxy) -1ndazoV 41.90 % after 4 hours

ITF-635 100 mg / kg oral protection none after 1 hour

41.70 % after 2 hours

(l- (4-Carbobutoxyphenyl) ~ 3- 50.00 % after 3 hours (y-p1per1dinopropoxy) indazole) 47.20 % after 4 hours

ITF-638 100 mg / kg oral protection 54.70 % after 1 hour

20.80 % after 2 hours

Jl- (4-carbobutoxyphenyl) -3- 23.90 % after 3 hours methoxylndazole) 30.80 % after 4 hours

-5-

009831/1935
BAD ORIQtNAL

c) Analgesic effect

The analgesic effect was determined according to the Randail-SeIUtO method on inflamed rat feet, using a device from BasHo _1, Milan.

The edema in the rat feet was caused by an intraplantar injection of 0.1 ml of a 20 % brewer's yeast suspension.

The animals used were male rats of the Wistar cultivar weighing from 160 to 80 g. All animals were first treated with brewer's yeast. After one hour the animals were divided into two groups, one of which served as a control group (ie only treatment with brewer's yeast) and the other of which were treated intraperitoneally with the substance to be examined in a dose of 50 mg / kg. All substances were suspended in 5% gum arabic. Before treatment with the substances, a reading was taken on the analgesimeter in order to determine the pain threshold in the various groups. Readings were taken at 1, 2, 3 and 4 hour intervals after treatment.

In connection with the substances according to the invention ™ The values obtained demonstrate a good analgesic effect, which in some cases up to the fourth hour lasted.

d) behavioral studies in mice

The behavioral studies were conducted with Hausen with a Weight of 20 g made.

All substances were injected intrapHtoneally. The following Doses were used in each group:

mg / kg - 200 mg / kg - 100 mg / kg - 50 mg / kg.

009831/1935 -6-

The animals were carefully observed for two hours. Only at the highest doses were cases of tonic and Tonic-clonic convulsions and an uncoordinated gait were observed. In most cases, those with the highest doses died treated animals within 24 hours.

With one substance, the 1- (4-carbobutoxyphenyl) -3-methoxy-indazole there was no death even at the highest dose.

Those treated with the lower doses (200, 100, 50 mg) Animals behaved completely normally in most cases and showed no particular observable symptoms.

009831/1935

Claims (4)

I) ^ namisikoiogiseh effective®-- lendazoi ^ erbiRdtip.g-, dsr -alIge · my formula (I). ; · "■. R ¹ where R © 1ne Ä-lfcyi group with 1 to 4 carbon atoms or a group of the formula. . ". -_ ■ denotes in the η an integer from 2 to 4, and where R "and R ¹ " can be the same or different and alkyl groups * each having 1 to 4 carbon atoms or together with dem.Stiefestoffatom a piperidine group, a morpholine group or a piperazine group can, while R ¹ denotes a hydrogen atom, a halogen atom or an alkyl or alcohol group having 1 to 4 carbon atoms. 00 98 31/193 5
8ADÖFUQINAL "8th- 2) 1- (4-carbobutoxyphenyl) = 3- (N, MiR] ßby1aminoethoxy) indazoi. 3) 1- (4 ~ carbobutoxypheriyl) "3- (ß 4) 1- (4-carbobutoxyphenyl) ~ 3 «(N JW indazole. δ) l- (4-Carbobutoxypheny1) -3 W 6) l = (Carbobutoxyphenyl) -3-methoxy-1nda2: oL 0098 31/1935 BAD ORiQiNAl