GB2024200A - A 1-benzyl-1H-indazol-3-il-3- (dimethyl amine)-propyl ether derivative and a process of producing same - Google Patents

Abstract

The 2-hydroxy benzoate derivative of 1-benzyl-1H-Indazol-3-il-3-(dimethyl amine)-propyl ether has the formula:- <IMAGE> and is produced by reacting under reflux an alcoholic solution of 1-benzyl- 1H-indazol-3-il-3-(dimethyl amine)- propyl ether with an alcoholic solution of 2-hydroxy benzoic acid for two hours followed by cooling for twelve hours. The compound has marked analgesic and anti-inflammatory effects.

Description

SPECIFICATION A 1-benzyl-1H-indazol-3-il-3(dimethylamine)-propyl ether derivative and a process of producing same This invention relates to a 1 -benzyl-1 H-indazol-3-il-3-(dimethylamine)-propyl ether derivative and to a process for producing same.

According to the present invention, there is provided the 2-hydroxy benzoate of 1 -benzyl-1 H-indazol-3-il-3- (dimethyl amine)-propyl ether which has pharmacological activity and which has the formula

The product is a stable white crystalline powder whose melting point is 94-96"C. The attached drawing, which is an infra-red spectrum of the compound shows the characteristic bands of the carboxylate ion and of tertiary amine salty NH+.

The product that is the subject of the invention is obtained by reaction of an alcoholic solution of 2-hydroxy benzoic acid with another alcoholic solution of 1-benzyl-1 H-indazol-3-il-3-(dimethyl amine)-propyl ether.

The invention also resides in the above compound for use in a method of treatment of the human or animal body and in a pharmaceutical composition comprising said compound, as an active ingredient, in combination with a pharmaceutically acceptable carrier or adjuvant.

Example In a round-bottomed distilling flask of 2 litres capacity with two-openingsr provided with reflux refrigerant and a funnel with key, 0.5 mols (69g) of 2-hydroxy benzoic acid is dissolved in 500 ml of ethanol. The mixture is caused to reflux while from the funnel 0.5 mols (155 g) of 1-benzyl-1H-indazol-3-il-3-(dimethyl amine)-propyl ether dissolved in 100 cc of ethanol is added drop by drop. Heating by reflux continues for two hours. At the end of this time the mixture is allowed to cool in a refrigerator at 0 C for 12 hours.

The crystals are filtered, washed with ethanol at 0 C and dried on filter paper. 180 g. of 0-hydroxy benzoate of 1-benzyl-1 H-indazol-3-il-3- (dimethyl amine)-propyl ether is obtained.

In the following sections we shall refer to the product that is the subject of this invention by the abbreviated form LIA-1032.

In experimental animals the effects have been determined of 6% LIA-1032 in local applications for pain induced by chemical and electrical stimuli, for inflammation (plantar edema caused by kaolin, contact edema caused by croton oil) and to capillary permeability. A solution of benzidamine hydrochloride at a molecular concentration equal to that of LIA-1032 was used as a control product.

The results with respect to pain induced by chemical stimulus (intraperitoneal acetic acid, "Whiting Test", Koster's method modified by Witkin and coworker, mouse) are shown in table I.

Table I Product Time Degree ofanalgesia 5' 58% LIA-1032 10' 60% 30' 54% 5' 45% Berizidamine HC I 10' 38% 30' 19% The results with respect to electrical stimulus (mouse tail, Radouco-Thomas method) are shown in table II.

Table II Product Time Degree ofanalgesia 5' 40% LIA-1 032 10' 50% 30' 70% 5' 50% Benzidamine HC I 10' 50% 30' 30% Plantar edema induced with kaolin in the foot of a rat (Wilhem and Domenjoz method) was markedly inhibited and its effect was persistent (table Ill) Table III Product Degree of inhibition 7h 2h 3h 4h 5h LIA-1 032 33% 32% 51% 39% 48% Benzidamine HC I 48% 22% 34% 20% 8% In the case of the contact edema caused by croton oil (rat, modified Selye method) the anti-inflammatory effect was even more marked and much more intense than that of the control product (see table IV).

Table IV Quantity ofproduct Product per ml of croton Degree ofinhibition oil 1 ml 91% LIA-1032 0.5 ml 95% 0.25 ml 96% 1 ml 40% Benzidamine HC i 0.5 ml 26% 0.25 ml 0% Table V shows the modifications that occurred in the capillary permeability on the depilated skin of the abdomen of a rabbit (in accordance with the modified Willoughby method); permeability has been studied both in the normal animal and in the animal treated at the same time with an irritant such as chloroform. It may be observed how LIAt1032 hardly modifies the capillary permeability and, in addition, it reduces the increase of permeability caused by chloroform.

Table V Increase of capillary permeability { /0)' Product 30' lh lh 30' 2h 2h 30' 3h 3h 30' 4h Controls 0. 0 0 0 0 0 0 0 LIA-1032 2.5 2.5- 2.5 2.5 7.5 7.5 0 0 Benzidamine HC I 0 0 0 0 0 0 0 0 Chloroform 55 57.5 60 60 60 60 60 60 LIA-1032 + Chloroform 32.5 45 45 52.5 50 55 37.S 37.5 Studies of local tolerance were carried out on the depilatedabdomen and on the conjunctiva of the rabbit.

No alterations were observed intheskin after an application of LIA-1032; the Banzidamine HO I produced an abundant flow of blood when it was applied in the form of an occlusive dressing. With both products there was reddening of the conjunctiva and lacrimation for the first 24 hours which in both cases completed remitted after 96 hours. No ulcerations or opacities were observed.

The DL50 (mouse) of the active principle was 1772 mg/kg administered orally.

The product has been studied in the clinic in spray form at 6%, 3 applications a day, in closed traumas of the soft tissues (especially contusions).

The first double blind experiment was carried out on 21 patients and has demonstrated the superiority of the product with respect to the placebo after 1 week of treatment. The global efficacy lanalgesic effect and anti-inflammatory affect) has been evaluated by means of an arbitrary scale from 0 to 3. The results obtained are shown in table VI.

Table Vl Product Placebo Number of patients 14 7 Average value 1.86 0.71 Standard deviation 1.18 1.03 t Student 1 .26g* * p < 0.05 The second experiment, also double blind, carried out on 24 patients has demonstrated that the analgesic efficacy of the product is superior to that of the placebo both after 4 days of treatment and after 7 days of treatment. A scale of 0 to 3 was also used as an evaluation system. The results are shown in table VII.

Table -Vll 4th day 7th day Product Placebo Product Placebo Numer of patients 17 7 17 7 Average value 1.52 0.71 2.41 1.28 Standard deviation 0.77 0.88 0.69 1.03 student 2.25* - 3.14** * p < 0.05 ** p < 0.01

Claims (4)

1. The 2-hydroxy benzoate of 1 -benzyl-1 H-indazol-3-il-3-(dimethyl amine)-propyl ether of the formula:

2. A process for obtaining the 2-hydroxy benzoate of 1 -benzyl-1 H-indazol-3-il-3-(dimethyl amine)-propyl ether comprising reacting an alcoholic solution of hydroxy-benzoic acid with a solution of 1-benzyl-1 Hindazol-3-il-3-(dimethyl amine)-propyl ether.

3. The compound of claim 1, for use in a method of treatment of the human or animal body.

4. A pharmaceutical preparation for topical use comprising the compound claimed in claim 1, as an active ingredient, in combination with a pharmaceutically acceptable carrier or adjuvant.