NO168378B - DEVICE FOR SUCTION OF GROUND AIR - Google Patents

Abstract

The invention relates to a device for drawing ground air under the foundation sole of a house. A rudder (1) is placed in an excavation made a few meters from the housing, and the lower end part of the rudder is open downwards and is provided with several rows of holes (2) through which a fan () arranged inside the rudder draws air. from the ground up. The extracted ground air flows out via a drain channel (7, 9) which opens above ground level (10). A cover () is arranged airtight at the upper end of the rudder. The outlet duct is connected to the rudder in an area (8) above the fan.

Description

Process for the production of new, therapeutically active indazol-3-yl-oxyalkanoic acids.

The present invention relates to a method for the production of new therapeutic agents

active (indazol-3-yl)-oxyalkanoic acid of the general formula I

where X = H, Cl, OCH3, N02, Nil,, NHCOCH3, R = H, phenyl, benzyl where phenyl and benzyl can be substituted with methyl, methoxyl, halogen, trifluoromethyl, dimethylsulfamyl, n = 1 or 2. Substances with formula I possesses interesting pharmacological properties and can be prepared by a) an alkali or alkaline earth salt of 3-oxy-indazole of the general formula II where R and X have the above meaning and Me denotes an alkali metal or the equivalent of a alkaline earth metal, is reacted with a halogen compound of formula III where R' denotes a carboxy, carbetoxy, nitrile or carboxyamide group and n is as stated above, to a compound of formula IV and when R' has a meaning different from carboxyl, the ester is hydrolysed , the nitrile or the amide of formula IV according to known methods, or b) in the special case of compounds of the general formula I where n — 2, the same compounds can also be obtained by reacting alkali salts of the general formula II with propiolactone, or c) compounds of the general formula I where R does not denote phenyl or substituted phenyl, are also obtained from the corresponding (indazol-3-yl)-oxyalkane derivatives without substituents in the 1-position by reacting the same derivatives with benzyl halides, which is optionally substituted as stated above in an alkaline aqueous medium, or d) compounds I where X denotes a nitro or amino group can also be obtained from the corresponding compounds, where X denotes hydrogen, by means of nitration and possible reduction of the nitro group to an amino group . In this nitration process, the nitro group enters the indazole-5 position.

According to the general synthesis scheme indicated here, the halogen compounds III, where R' is a carboxyl group, are allowed to react with the alkali salts (preferably the sodium salt) of 3-oxyindazoles in aqueous solution at temperatures and over time periods that depend on the individual starting substances , which however generally varies between 20° and 80°C and from 1 to 5 hours. A suitable method is also that in which the alkali salt of the 3-oxyindazole is reacted with the sodium salt of chloroalkanoic acid in a toluene or xylene suspension by boiling from 1 to 5 hours. When R' denotes a carbolic, nitrile or carboxyamide group, the reaction of the halogen derivatives III with compounds II is carried out in an inert solvent (e.g. dioxane). Subsequent hydrolysis to carboxyl derivatives is carried out according to known methods.

The reaction between the alkali salt of 3-oxyindazoles of general formula II and propiolactone is carried out in an aqueous medium at temperatures between 50° and 100°C.

In the above-mentioned reactions, in addition to the derivatives with formula I, compounds corresponding to formula Ia can also be used

is formed, where the acetic or propion residue is bound to nitrogen in the 2-position rather than to oxygen. By choosing suitable reaction conditions, however, it is possible to isolate compounds I in a pure state and with a yield of up to 80 per cent.

Derivatives of formula I are distinguished from compounds Ia by means of the IR spectrum. They show an intense band at around 1,530 cm<1>, which represents the most intense band that the spectra of compounds Ia have. The melting points of compounds I are usually lower than those of the corresponding compounds Ia.

The (indazol-3-yl)-oxyalkanoic acids I exhibit

interesting pharmacological properties.

The following methods have been used for

pharmacological investigations:

Acute toxicity was determined in mice by the intraperitoneal route by recording mortality occurring within 5 days following treatment. A series of behavioral observations were then made using the Irwing method (1964). Neurovegetative effects have been investigated in vitro by recording the response of guinea pig isolated intestine stimulated with acetylcholine, histamine and DMPP as well as in vivo by recording the arterial pressure and response to adrenaline injection and visceral stimulation in a cat anesthetized with chloralose (70 mg/kg i.p.). Analgesic effect was then investigated according to the method of Sigmund and colleagues (1957).

The anti-aedoma effect in rats has been investigated according to the method of Winter et al. (1962) and the anti-granuloma effect according to the method of Meier et al. (1950).

Moreover, investigations have been made for said derivatives on the denaturation of serum albumin which is obtained with the aid of heat (Mizushima, 1963; Mizushima and Suzuki, 1965; Del Basso and Silvestrini.

Local anti-inflammatory action has been investigated using the method of applying the products to the granuloma (Winter et al., 1962) and applying the products in a 3% suspension in vaseline to the blister obtained using the Parrat and West method (1958).

Local tolerance was determined either by application to the skin tissue in rats or by subcutaneous injection in rats.

Products with formula I exhibit very low acute toxicity of approx. 300 mg/kg i.p. with the exception of (1-o-chlorobenzyl-indazol-3-yl)-oxyacetic acid which is approx. twice as toxic.

Behavioral effects consist of sedative effects at relatively high doses (50 to 100 mg/kg i.p.) and exhaustion and convulsions at subtoxic doses. No neurovegetative effects were found either in these tests or in those performed using isolated organs and pressor response in cats. The analgesic effect with the test of Sigmund et al was found to be lacking, except in (1-m.chlorobenzyl-indazol-3-yl)-oxyacetic acid which shows a considerable effect with doses of 10 mg/kg s.c.

The anti-oedema effect is lacking, and likewise the effect on granuloma is weak or non-existent.

In contrast, all the products exhibit anti-inflammatory effects on contact comparable to or higher than that of cortisone. In reality, they not only inhibit granuloma development when applied directly to a cotton ball, but also definitely reduce the local inflammatory reactions when applied as 3 percent ointments.

This result is particularly interesting as, as far as is known, a local anti-inflammatory effect is described for the first time with substances that are not of the steroid type. Between the lowest active concentration and that which produces irritation phenomena, there is a range that goes from 1 to 20 and 1 to 50.

Local anti-inflammatory action is probably associated with the ability of said substances to protect serum albumin from heat denaturation. On the other hand, it is known that in a number of inflammatory processes a denaturation of proteins occurs, which in turn is responsible for the many phenomena that characterize the inflammatory process.

Moreover, as all known anti-rheumatic drugs are capable of inhibiting albumin heat denaturation, said substances may be considered capable of exerting therapeutic action in rheumatic conditions, in which anomalous proteins analogous to those formed by heating of albumin in v i t r o, appears in the blood.

EXAMPLE I

(1-p.Chlorobenzyl-indazol-3-yl)-oxyacetic acid

An aqueous solution of 1-p.chlorobenzyl-3-oxy-indazole potassium salt is prepared by dissolving 25.8 g of the substance in 200 ml of 14% KOH solution. It is heated on a water bath, and 35 g of mono-bromo-acetic acid are added at once while stirring. Heating and stirring are continued until the solution pH has dropped to 7, which occurs in about y2 hours. After cooling, any small undissolved residue is filtered off and then acidified with diluted HC1. The precipitate is collected, washed with water and dissolved in K2C03°S 10% aqueous solution. A small undissolved residue is filtered off and then acidified again. The (1-p.chlorobenzyl-indazol-3-yl)-oxyacetic acid is now dissolved in a slight excess of sodium bicarbonate in an aqueous saturated solution and combined again by acidification. It is then washed with water and crystallized from 95°C alcohol. The substance has s.p. 117°C. Small amounts of the isomeric (1-p.-chlorobenzyl-indazol-3-en-2-yl)-acetic acid occur in the crystallization liquids.

EXAMPLE II

(1-Benzyl-indazol-3-yl)-oxyacetic acid

a) 246 g of l-benzyl-3-oxy-indazole sodium salt and 131 g of chloracetamide are suspended in 1 liter

dioxane and heated under reflux for 2 hours. The solvent is removed under reduced pressure and the residue is crystallized from alcohol. The (1-benzyl-indazol-3-yl)-oxyacetic acid amide is obtained in this way and has m.p. 135-137°C.

b) 155 g of the amide is refluxed for 2 hours with a mixture of 300 ml of dioxane and 300

ml of concentrated hydrochloric acid. After cooling, add

3 liters of water. An oil precipitates and solidifies

soon. It is crystallized from acetone, filtered

then hot from some undissolved l-benzyl-3-oxy-indazole. (1-Benzyl-indazol-3-yl)-oxyacetic acid melts at 160°C.

EXAMPLE nine (1-Benzyl-indazol-3-yl)-oxyacetic acid e

a) 11 g of 1-benzyl-3-oxy-indazole sodium salt are dissolved in 70 ml of absolute alcohol by heating

for boiling while stirring; a solution of 3.5 g of chloroacetonitrile in 5 ml of absolute ethanol is then introduced over the course of 2-3 minutes, and after 10 minutes a second portion of 1.7 g of chloroacetonitrile is added; the reaction is finally completed by further boiling for 45 minutes. The mixture is allowed to cool at room temperature and then filtered; the alcoholic solution is concentrated to dryness under reduced pressure, the residue is again taken up in 1 ether and the ethereal solution is washed in order with dilute HCl, with HgO, with NaOH and with HgO. It is dried over Na 2 SO 4 , and the solvent is removed. The residue consists of (1-benzyl-indazol-3-yl)-oxyacetonitrile which is crystallized from methanol and has m.p. 93°C.

Analysis:

b) 1 g of the thus prepared and well pulverized (1-benzyl-indazol-3-yl)-oxyacetonitrile

is added with stirring to concentrated HC1. It is heated in a boiling water bath for 2-3 minutes, whereby the product first melts and then soon solidifies. After cooling, the precipitate is filtered off and then washed carefully with water in a mortar. It is dissolved in 10 per cent Na2C08 and combined again with dilute HC1. (1-Benzyl-indazol-3-yl)-oxyacetic acid has m.p. 160°C (from ethanol).

EXAMPLE IV

(1-m.Chlorobenzyl-indazol-3-yl)-oxyacetic acid

a) 25.8 g of 1-m.chlorobenzyl-3-oxy-indazole are dissolved in a sodium methylate solution which is prepared from 2.3 g of sodium. On removal of the solvent, 1-m.chlorobenzyl-3-oxy-indazole sodium salt remains, which is mixed with 16.7 g of ethyl bromoacetate and suspended in 280 ml of 1,2-dimethoxyethane. It is stirred and heated for 3 hours while stirring at 100°C. After cooling, the precipitate is filtered off and the filtrate is concentrated to dryness under reduced pressure. The residue is again taken up in ether and first washed carefully in a very dilute aqueous NaOH solution, then in water. It is dried over Na2SO4, and the solvent is removed. Distillation under reduced pressure has a mixture of a greater proportion of (1-m.chlorobenzyl-indazol-3-yl)-oxyacetic acid ethyl ester and (1-m.chlorobenzyl-indazol-3-en-2-yl)-acetic acid ethyl ester which boils at 218°C/1.5 Torr.

Analysis:

b) Hydrolysis of the ester just described is carried out by treatment with 2 equivalents of

NaOH dissolved in a volume of water equal to twice the weight of the ester with stirring at 90°C until complete dissolution. After approx. one hour the reaction is complete. It is cooled and acidified with dilute HC1. The precipitate is collected and purified by dissolving it in Na2C03; a small insoluble residue is filtered off. During acidification, a mixture of 2 isomers is obtained, where, however, (1-m.chloro-benzyl-indazol-3-yl)-oxyacetic acid is predominant. For the purification, the advantage is taken of the fact that (1-m.chlorobenzyl-indazol-3-en-2-yl)-acetic acid is slightly soluble in alcohol. Therefore, by treating the mixture with alcohol, only (1-m. chlorobenzyl-indazol-3-yl)-oxyacetic acid is extracted. It is finally crystallized from hexane; s.p. 109°C.

EXAMPLE V

(3-(Benzyl-indazol-3-yl)-oxypropionic acid

25 g of 1-benzyl-3-oxy-indazole sodium salt are dissolved in a solution of 3 g of NaOH in 75 ml of water. The solution is heated to 65°-70°C, and 11.7 g of propiolactone are added slowly while stirring. At the end of the addition, it is heated for a further 15 minutes and cooled to room temperature. It is acidified and extracted with ether. Some unreacted 1-benzyl-3-oxy-indazole precipitates from the ethereal solution. The 3-(1-Benzyl-indazol-3-yl)-oxypropionic acid is filtered and extracted with 5% bicarbonate solution and then combined again by acidification with HC1. It is crystallized from benzene. 15 g of substance is thus obtained and has a m.p. 135°C.

EXAMPLE VI

(l-Benzyl-5-nitro-indazol-3-yl)-ox<y>acetic<y>re

20 g of (1-benzyl-indazol-3-yl)-oxyacetic acid are suspended in 200 ml of acetic anhydride. It is cooled to 0°C, and 3.4 ml of HN03 with a specific gravity of 1.52 is slowly added dropwise. It is stirred for 3 hours, until complete dissolution is obtained; precipitation of the nitro derivative follows. It is filtered, washed with water and crystallized from benzene, m.p. 155 °C.

EXAMPLE VII

( 5 - Ace tamino -1 - benzy 1 - indazol - 3 - yl) - oxyacetic acid

a) To a solution heated to 80 °C in a water bath and stirred with 30 g of SnCl2.H20, add

in 30 cm<3> of concentrated HCl 14 g of (1-benzyl-5-nitro-indazol-3-yl)-oxyacetic acid in portions; the compound unlocks and then remains partially insoluble. At the end of the addition, the reaction is completed by heating for 15 minutes at 80°C, then it is cooled, and the precipitate is separated, from which by crystallization from alcohol-ether (5-amino-1-benzyl-indazol-3-yl)-oxy- acetic acid hydrochloride is obtained.

The hydrochloric mother liquors are diluted with water and brought to pH8; the precipitate of inorganic salt is separated, while the alkaline solution is neutralized at pH6 with acetic acid. The precipitate that forms is filtered off, washed and crystallized from dioxane-methanol (1:1). (5-Amino-1-benzyl-indazol-3-yl)-oxyacetic acid melts at 217°C (decomposition).

b) 6 g of (5-amino-1-benzyl-indazol-3-yl)-oxyacetic acid in 24 ml of acetic anhydride are heated

for 15 minutes at 110°C. It is poured into 1100 ml of H 2 O, and the resulting solution is slowly made alkaline with aqueous Na 2 CO 3 . It is clarified with activated charcoal, then filtered and acidified with diluted HC1. The precipitate is filtered, washed with H 2 O to neutrality and crystallized from ethanol. In this way, (5-acetamino-1-benzyl-indazol-3-yl)-oxyacetic acid is obtained, which melts at 238°C.

EXAMPLE VIII

[1-(2,6-dimethyl-3-dimethylsulfamoyl)-phenyl-indazol-3-yl]-oxyacetic acid 6 g of N-(2,6-dimethyl-3-dimethylsulfamoyl)-phenyl-anthranilic acid are dissolved in 42 ml acetic acid. 6 g of NaN02 is added and it is allowed to stand overnight. It is poured into water and allowed to react until the precipitate assumes a solid appearance. It is filtered, washed with water and then repeatedly with benzene. In this way the N-(2,6-dimethyl-3-dimethyl-sulfamoyl)-phenyl-N-nitroso-anthranilic acid is obtained, which has a m.p. 139°C (decomposition).

5.7 g of zinc powder are suspended in 22 ml of water.

While stirring and by keeping the temperature between 10° and 20°C, a solution of 10 g of nitroso derivative in 100 ml of acetic acid is introduced slowly. At the end of the reaction, it is stirred further for approx. 2 hours, then heated for 10 minutes at 80°C and poured into 150 ml of water. The pH is brought to 6 with solid sodium carbonate, and the precipitate is filtered off. After crystallization from alcohol is obtained

The 1-(2,6-dimethyl-3-dimethylsulfamoyl)-phenyl-3-oxy-indazole melting at 182°C.

The oxy-indazole is converted to the sodium salt with the calculated amount of sodium methylate. One equivalent of this salt, 1.1 equivalents of dry sodium chloroacetate and 11 parts of xylene are heated to boiling for 4-5 hours. It is cooled and extracted with 1% NaOH. It is acidified with hydrochloric acid and extracted with ether. From the etheric up-

the solution is extracted [1-(2,6-dimethyl-3-dimethylsulfamoyl)-phenyl-indazol-3-yl]-oxyacetic acid

with 7 percent sodium bicarbonate. During surgery

precipitates the almost pure substance and can be crystallized from ligroin, m.p. 120-1°C.

According to one or more of the aforementioned methods

the following compounds have been prepared:

(1-phenyl-indazol-3-yl)-oxyacetic acid,

s.p. 164°

(1-m.chlorophenyl-indazol-3-yl)-oxyacetic acid,

s.p. 148°

(the intermediate 1-m.chlorophenyl-3-oxy-indazole, not described in the literature, has m.p. 240°)

(1-m.trifluoromethylphenyl-indazol-3-yl)-oxyacetic acid, m.p. 156°

(the intermediate 1 -m.trifluoromethylphenyl-3 -

oxyindazole, not described, has s.p. 203°)

(1-o.chlorobenzyl-indazol-3-yl)-oxyacetic acid,

s.p. 156°

(1-benzyl-6-chloro-indazol-3-yl)-oxyacetic acid, m.p. 157°

[1-(2,6-dimethylphenyl)-indazol-3-yl]-oxyacetic acid, m.p. 130°

[1-(2,3-dimethylphenyl)-indazol-3-yl]-oxyacetic acid, m.p. 142°

p-(1-phenyl-indazol-3-yl)-oxypropionic acid,

s.p. 131°

|3-(indazol-3-yl)-oxypropionic acid, m.p. 179°

P-(1-p.fluorophenyl-indazol-3-yl)-oxypropionic acid, m.p. 150-2°

(the intermediate l-p.fluorophenyl-3-oxy-indazole, not described, has m.p. 250°)

|3-(1-m.bromophenyl-indazol-3-yl)-oxypropionic acid, m.p. 89°

(the intermediate 1-m.bromophenyl-3-oxy-indazole, not described, has m.p. 242°)

p-(5-methoxy-indazol-3-yl)-oxypropionic acid,

s.p. 184°

5-chloro-1-benzyl-indazole-3-oxyacetic acid,

s.p. 158°

p-[1-(2,6-dimethyl)-phenyl-indazol-3-yl]-oxy-propionic acid, m.p. 133°

(5-amino-1-benzyl-indazol-3-yl)-oxy-acetic acid hydrochloride, m.p. 230°.

Claims (1)

1. Process for the production of new, therapeutically active (indazol-3-yl)-oxyalkanoic acids of the general formula (I) where X denotes H, Cl, OCH3, NOa, NEL,, NHCOCH3; R denotes H, phenyl, benzyl, Whereas phenyl and benzyl can be substituted by methyl, halogen, trifluoromethyl, dimethylsulfamyl; n represents 1 or 2; Hal denotes halogen and Me denotes an alkali metal, characterized in that a) an alkalizate of a 3-oxyindazole with the general formula (II) is reacted with a halogen compound of the general formula (III) where R' denotes a carboxy, carbetoxy, nitrile or carboxyamide group, upon which a compound of the general formula (IV) is formed, and when R' has a meaning different from carboxyl, the ester, nitrile or amide with the general formula (IV) is hydrolysed according to known methods, or b) where n = 2, by an alkali salt of 3-oxy-indazole with the general formula (II) is reacted with propiolactone, or c) where R does not denote phenyl or substituted phenyl, in that the corresponding (indazol-3-yl)-oxyalkanoic acids without substituents in the 1-position are reacted with optionally substituted benzyl halides, or d) where X denotes a nitro or amino group, in that the corresponding compounds, where X denotes hydrogen, are subjected to nitration and eventual reduction of the nitro group to an amino group.