CH601228A5 - Antiinflammatory indomethacin esters active topically and orally - Google Patents

Abstract

Antiinflammatory indomethacin esters active topically and orally prepd. e.g. by esterifying indomethacin with e.g. (3)-pyridyl-methanol (NL 27.12.77)

Description

  

  
 



   The present invention relates to a process for preparing novel derivatives of esters of indolacetic acid, represented by the general formula A:
EMI1.1
 wherein n represents an integer of 1 to 3, and R is hydroxyl, halogen, trihalomethyl, alkoxy, acyloxy, substituted phenyl, pyridyl or substituted pyridyl.



   In the general formula A above, R can be more precisely: chlorine, fluorine, bromine or iodine; trichioromethyl or trifluoromethyl; lower alkoxy, in particular methoxy, ethoxy or propoxy; lower acyloxy, for example acetoxy or propionyloxy; phenyl substituted in various positions by 1 or 2 substituents, in particular chlorine, fluorine, bromine, iodine, lower allyl, for example methyl and ethyl, lower alkoxy, for example methoxy and ethoxy, nitro or trifluoromethyl; pyridyl-2, pyridyl-3 or pyridyl-4, substituted in various positions with 1 or 2 substituents, in particular chlorine, bromine, fluorine, iodine and methyl.



   Anti-inflammatory agents for external use are mostly adrenocortical hormones. However, long term use of these steroid preparations often causes significant side effects. This is why, in the medical field, the need has appeared to have anti-inflammatory agents of local use, of less toxicity. Thus, according to the present invention, various new compounds have been synthesized, taking into account the development of the preparation of anti-inflammatory agents for local use other than steroids. The process according to the invention relates to the preparation of derivatives of indolacetic acid esters mentioned above, and which have a high degree of analgesic and anti-inflammatory activities, both orally and for local use.

  All the compounds according to the present invention are new and do not appear in any publication published to date, and as they have great analgesic and anti-inflammatory activity, without side effects on the gastrointestinal tract when ingested orally, they can be interesting drugs.



   The process according to the invention for the preparation of the compounds of formula A mentioned above consists in reacting the N '- (pchlorobenzoyl) N' - (p-methoxyphenyl) hydrazine of general formula I, its salts or its hydrazonic derivatives:
EMI1.2
 with a compound of general formula II:
EMI1.3
 where n and R have the same meaning as in formula A.



   The reaction scheme of the process according to the invention is as follows:
EMI1.4

 In this process, the N '- (p-chlorobenzoyl) N' - (p-methoxyphenyl) hydrazine of formula I, one of its salts (for example hydrochloride or phosphate), or one of its hydrazonic derivatives (for example benzaldehyde- or acetaldehyde-N '- (p-chlorobenzoyl)
N '- (p-methoxyphenyl) hydrazone, is reacted with an ester derivative of levulic acid. This reaction is carried out in organic acids, for example acetic or propionic acid, or in organic solvents, in particular benzene, toluene, xylene, dioxane, diisopropyl oxide, acetonitrile, propanol, butanol or ethylene glycol ether, in l 'absence or presence of a condensing agent, by heating to 60 "-140" C.



  In particular, mineral acids, for example hydrochloric or sulfuric acid, metal halides in particular zinc or copper chloride, borofluorides and polyphosphoric acids are suitable as condensation agents. The reaction can even take place in the absence of a solvent.



   A certain number of compounds obtained by the process according to the invention, accompanied by their melting point, are collated in Table I.



  Table I
EMI2.1

EMI2.2


<tb> Compound <SEP> n <SEP> R <SEP> Point
<tb> N "<SEP> of <SEP> merge
<tb> <SEP> (0C)
<tb> <SEP> 2 <SEP> 2 <SEP> -OH <SEP> 106-107
<tb> <SEP> 2 <SEP> 1 <SEP> -CF3 <SEP> 97- <SEP> 98
<tb> <SEP> 3 <SEP> 1 <SEP> -OCH3 <SEP> 98- <SEP> 99
<tb> <SEP> 4 <SEP> 2 <SEP> -OCH3 <SEP> 68- <SEP> 69
<tb> <SEP> 5 <SEP> 1 <SEP> - <SEP> OC2Hs <SEP> 62- <SEP> 63
<tb> <SEP> 6 <SEP> 2 <SEP> - <SEP> OC2Hs <SEP> 77- <SEP> 78
<tb> <SEP> 7 <SEP> 2 <SEP> -OCOCH3 <SEP> 119-121
<tb> <SEP> 8 <SEP> 1-C1 <SEP> 113-114
<tb> <SEP> 9 <SEP> 1
<tb> <SEP> F,
<tb> <SEP> F
<tb> 10 <SEP> 1 <SEP> d
<tb> <SEP> 97- <SEP> 98
<tb> 11 <SEP> 1 <SEP> 1F <SEP> 122-123
<tb> 12 <SEP> 2 <SEP> 2-F <SEP> 117-118
<tb> <SEP> CH3
<tb> 13 <SEP> 1 <SEP> -> t <SEP> 143-144
<tb> <SEP> CH3
<tb> 14 <SEP> 1 <SEP> - <SEP> 92-93
<tb> 15 <SEP> 1 <SEP> --CH3 <SEP> 120-121
<tb> <SEP> CF
<tb> 16 <SEP>

   1 <SEP> O <SEP> 66- <SEP> 67
<tb> <SEP> CF
<tb> 17 <SEP> 1 <SEP> - <SEP> 88- <SEP> 89
<tb> <SEP> Nn
<tb> 18 <SEP> 1 <SEP> - <SEP> 95- <SEP> 96
<tb> 19 <SEP> 1 <SEP> e <SEP> 116-118
<tb> <SEP> Clin
<tb> 20 <SEP> I <SEP> 119-121
<tb>
 The acute toxicity of the compounds prepared by the process according to the invention was first studied, then their anti-inflammatory activity. In addition, the ulcerogenic activity which is found in conventional anti-inflammatory agents other than steroids was also examined. It has been found that some of the compounds prepared according to the invention exhibit high degree pharmacological activities with low toxicity. The tests are carried out as follows and their results collated in Table II.



     1. Acute toxicity
 The test compound, suspended in a 1% tragacanth saline solution, is administered intraperitoneally or orally to male mice of ddY strain (16-24 g).



  The lethal dose is determined from the number of animals that died 72 hours after administration.



  2. Oral anti-inflammatory activity
 To a group of 5 male rats of the Wistar strain (100-150 g), each test compound, suspended in 0.5% saline tragacanth solution, was administered orally.



  After 1 h, a 1% carrageenin suspension in water is injected into the hind paw, subcutaneously. After 3 h, the volume of the edema caused by carrageenan is measured, and the percentage inhibition is determined by comparison with the results obtained in the control animals. In order to compare, the percentage inhibition of each compound tested is divided by that of the reference compound, indomethacine ((p-chlorobenzoyl) -1 methyl-2-methoxy-3-indolyl-3 acetic acid), which gives the relative inhibition reported in Table II. The average percentage of inhibition caused by indomethacin is 41.1% at a dose of 10 mg / kg.



  3. Ulcerogenic activity on the rat stomach
 Male Wistar rats weighing 200-220 g are fasted for 24 h. Indomethacin and the products tested are suspended in a 0.5% solution of tragacanth, and these solutions are given to animals orally at a dose of 20 mg / kg. The animals are sacrificed in ether 18 hours after administration. The excised stomachs are filled with a 1% formalin solution, and the whole is immersed in a 1% formalin solution for fixation. Then, an incision is made parallel to the greater curvature to examine if there has been erosion or ulcer. The degree of erosion and ulcer is represented by the value of its area (mm2).

 

   Table II shows the pharmacological effects, as well as the acute toxicity of certain compounds prepared by the process according to the invention designated by the number which they bear in Table I, and, by way of comparison, of indo methacin.



   Table II
Compound Action anti- Sign Acute toxicity (NO) inflammatory oral ulcer
 orally gastric (mg / kg)
 (10 mg / kg) (mm2)
Indomethacin 1.0 6.75 + 1.98 10-20
 9 0.76 0.50 + 0.30> 500
 10 0.68 0.50 + 0.38> 500
 11 0.41 0.13 + 0.08> 500
 13 - 0.19 + 0.13> 500
 14 - 013 + 008 200-500
 15 1.00 0.88 + 0.39 500
 The following examples constitute an illustration of the process according to the invention.



  Example 1:
 A mixture of 1 g of Nt chlorobenzoyl hydrochloride)
N '- (p-methoxyphenyl) hydrazine, 0.85 g of p-methylbenzyl levulate and 6 ml of glacial acetic acid, is reacted at 80 ° C for 3 h. When the reaction is complete, the solvent is removed. of the mixture by distillation under reduced pressure, leaving a residue. This residue is added with ice-water, then extracted with ether. The ethereal extract is washed with 5% sodium bicarbonate and with water, The ether is then distilled off and the residue is passed through a column of silica gel, the adsorbate is then eluted with ether.

  The first effluent is concentrated and gives, by cooling to room temperature, 1.32 g of (p-chlorobenzoyl) -1 methyl-2-methoxy-5-indolyl-3 p-methylbenzyl acetate, in the form of colorless needles, melting at 1190. -1200C.



   Mass spectrum: parent ion 461 m / e.



  Example 2:
 A mixture of 1 g of N '- (p-chlorobenzoyl) hydrochloride
N '(p-methoxyphenyl) hydrazine, 0.93 g of p-chlorobenzyl levulate and 6 ml of glacial acetic acid, is reacted at 80 ° C for 3 h. When the reaction is complete, the solvent is removed. by distillation under reduced pressure, and to the residue is added ice-water; the whole is extracted with ether. The ethereal extract is washed with a 5% solution of sodium bicarbonate and water. , then is dehydrated.

  The ether is removed by evaporation and the residue is recrystallized from a solvent mixture of ether and diisopropyl ether, to give 1.35 g of (p-chlorobenzoyl) -1 methyl-2-methoxy-5 indolyl -3 p-chlorobenzyl acetate, in the form of colorless needles, melting at 113 "-114" C.



   Mass spectrum: parent ion 481 m / e.

 

Claims (1)

CLAIM Process for the preparation of indolacetic acid ester derivatives of the general formula: EMI3.1 in which n can be an integer from 1 to 3, and R can be hydroxyl, halogen, trihalomethyl, alkoxy, acyloxy, substituted phenyl, pyridyl or substituted pyridyl, characterized in that it consists in reacting N '- ( p-chlorobenzoyl) N '- (pmethoxyphenyl) hydrazine of the formula: EMI3.2 with a compound of general formula: EMI3.3 in which n and R have the same meaning as above. SUB-CLAIMS 1. Method according to claim characterized in that R is preferably trifluoromethyl, methoxy, ethoxy, acetoxy, hydroxy, phenyl substituted with chlorine, fluorine, methyl or trifluoromethyl in various positions, pyridyl and chloropyridyl. 2. Method according to claim, characterized in that one operates between 60 and 1400 C, preferably around 800 C. 3. Method according to claim, characterized in that one operates in a solvent which is an organic acid, such as acetic acid, or an organic solvent. 4. Method according to claim, characterized in that one operates in the presence of a condensing agent. 5. Method according to claim, characterized in that the starting hydrazine is in the form of one of its salts or one of its hydrazonic derivatives.