FR2505183A1 - NOVEL ANTI-ALLERGIC COMPOSITION BASED ON N-BUTYL (OR N-PENTYL) -4-CYCLOHEXANE CARBOXYLIC ACID - Google Patents

Abstract

NEW ANTI-ALLERGIC COMPOSITION. IT INCLUDES AS AN ACTIVE PRINCIPLE, A COMPOUND REPRESENTED BY THE GENERAL FORMULA (CF DRAWING IN BOPI) IN WHICH R REPRESENTS THE N-BUTYL OR N-PENTYL GROUP. ANTI-ALLERGIC MEDICINE.

Description

The present invention relates to a novel composition

  antiallergic and more particularly an anti-allergenic composition

  allergic agent comprising, as active principle, a compound represented by the COOH formula

  wherein R is n-butyl or n-pentyl.

  So far, glucocorticosteroids have been widely used in medicine for the treatment of allergic diseases such as allergic endocrinosis, rheumatoid arthritis, collagen disease, allergic nephritis, allergic hemopathy, allergic digestive diseases, disorders

  hepatic allergies, dermatitis and bronchial asthma.

  However, such steroid compositions have serious drawbacks because, when they are usually administered for long periods, they have side effects, namely the appearance or aggravation of infectious diseases, the appearance of various diseases due to anasarca and insufficiencies

  adrenal and also the appearance of gastrointestinal disorders.

  As a result, the usual use of steroid compositions is now considered

  as undesirable and tends to be avoided.

  During attempts to develop non-steroidal antiallergic substances and

  effective in the treatment of the various diseases listed below.

  above, the Applicant has synthesized a number of

  compounds-and studied their pharmacological activities.

  The compounds represented by the general formula (I) exhibit the following pharmacological effects: improvement of the liver function, anti-fibrinolytic action, anti-ulcerative action, hypo-reaction to the immune effect, normalizing action and these compounds are useful as improving agents

  liver function, anti-fibrinolytic agent and anti-

  These compounds are also useful as drugs for the treatment of allergic diseases caused by abnormal immune function, diseases such as rheumatoid arthritis, autoimmune disorders, asthma, allergic nephritis, allergic rhinitis,

  atopic dermatitis, gastroenteric allergy and anaphylaxis.

  As is apparent from the foregoing, the anti-allergic compositions according to the present invention not only include drugs having anti-allergic actions in the narrow sense of the term, but also drugs having anti-allergic actions in the sense of the invention. term and including, among others, the various actions mentioned above. The compounds which constitute the active principle of the anti-allergic compositions according to the present invention, and which are represented by the general formula (I) above, are crystalline in nature and can be prepared by the usual methods, with a view to to obtain capsules, granules, pills, powders, tablets, syrups, tinctures, injections, suppositories, ointments, plasters, poultices, compositions deposited on tape and the like These preparations may be

  used internally (oral) and externally.

  The pharmaceutically acceptable carriers that can be used for these compositions include glucose, sucrose, lactose, millet jelly and honey; cellulosic or starchy materials, such as methyl cellulose,

  crystalline cellulose, carboxymethylcellulose, hydroxypropyl

  pylcellulose, corn starch and potato starch and natural plant gum resins such as gum arabic and gum tragacanth. As a support, it is possible to

  also liquefied spray, the crude extract of gly-

  cyrrhiza, powdered gentian, gentian extract, dry yeast, yeast extract, gelatin, agar-agar

  pulverized propylene glycol, glycerin, polyvinylpyrrolidone

  lidone, sorbitol, water, alcohols,

  suspension, the emulsifying agents, the surfactants

  active ingredients, calcium levtearate, magnesium stearate,

  Methyl oxybenzoate, silicone and talc The supports enumerated above may be used alone or in combination depending on the state and the form of the compositions which it is desired to obtain,

  using the usual pharmaceutically acceptable methods.

  The compounds of formula (I) with anti-allergic action can be administered in humans at doses of 50 to 900 mg / day. The compounds of formula (I) which constitute the active principle of the antiallergic compositions according to the present invention and as indicated in Table I below, have been described as being useful for certain uses other than medicinal uses in "Z Chem 219 ( 1972) "In

  furthermore, these compounds of formula (I) can be easily synthesized

  by the method described in the above review.

TABLE I

  COOH Active ingredient of the composition according to the invention, represented by the general formula (I): R Compound n Type of isomer R Existing geometric literature The anti-allergic actiors exhibited by the anti-allergic compositions according to the present invention are

  established by the pharmacological experiment below.

  Homologous passive cutaneous anaphylaxis (homologous PCA) in the rat In accordance with the protocols of Tada, T et al (J Immunol, 106, 1002, 1971), the passive passive cutaneous anaphylaxis (homologous PCA) reaction test is performed on male rats of the Wistar strain, each of these rats weighing 160 to 170 grams In this test, the DNP-As (Dinitrophenol coupled with

  an extract of Ascaris suum) obtained by reaction of the dinitrogen

  phenol (DNP) with a protein extracted from Ascaris suum and is used as an antigen. Furthermore, a 1 1 Trans (CH 2) 3 CH 3 Z Chem 219 (1972) is prepared.

2 "(CH 2) 4 CH 3

  anti-DNP-As rat serum using said antigen and is used as an antibody. The latter having a sufficient titre is injected intradermally into three sites, at a rate of 0.1 ml per site, located on one side the shaved back of each rat; in addition, the same dose of saline solution (saline solution) is similarly injected into three sites on the other side of the back for comparison or correction of possible experimental errors. 48 hours, 1.0 ml of an antigen solution (amount of protein: 2.0 mg) containing 0.25% Evans blue were administered by intravenous injection to each test animal 30 minutes later. sacrifices the rats by rendering them exanguated and their skin is removed in order to measure the surface of the PCA bluing lesion. The amounts of extravasated dye are then measured according to the method proposed by

  Harada, M et al (J Pharm Pharmacol, 23, 218, 1971).

  The compounds of formula (I) are administered orally

  in rats at doses of 200 mg / kg 2 hours before administration.

antigen.

  The results obtained are listed in Table II below.

TABLE II

  Surface area Rate Quantity of inhibitory colo

  tested n occupied by extravasated dinhi rant tion dye extra ini vasé (mm 2) bition (, uglsite)

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (%)

Witness 99.11 + 3.54 14.36 + 0.83 -

  1 76.87 + 2.68 22.4 5.17 + 0.32 64.0

  2 67.20 + 2.57 32.2 2.49 + 0.29 82.7

  B Rat test for reverse cutaneous anaphylaxis

  According to the Yamazaki protocol (Folia Pharmacol Jap.

  , 65, 1964) developed by improving the Ungar protocol and

  coll (Arch intern Pharmacodyn 123, 71, 1959), one tests,

  indicated below, male rats of Wistar strain weighing

each about 100 g.

  First, rabbit anti-rat serum is dissolved in 0.5% Evans blue solution to obtain a 15% serum solution. The latter is injected intradermally into two sites, at a rate of 0.05 ml per site, located on one side of the back of each of the rats, while a 0.5% solution of Evans blue in saline is similarly injected

  0.05 ml per site, located on the other side of the rats' backs.

  2 hours later, the test animals are sacrificed and their skin removed The stains marked with Evans blue are cut to separate the oedematous (swollen) parts

the weight is then determined.

  The intensity of intumescence is calculated according to the following formula:

W W

  I (%) = 1 x 100 Ws in which Wi denotes the poic of the inflamed part and

  Ws is the weight of the control part.

  The anti-allergic compounds of formula (I) according to the present invention are administered in the rat orally at a dose of 100 mg / kg 1 hour before the injection of rabbit anti-rat serum. The results obtained are

  listed in Table III below.

TABLE III

  C Release of histamine by a guinea pig lung fragment The lungs of guinea pigs actively sensitized with ovalbumin are totally irrigated with a Tyrode solution and then cut to obtain samples with a thickness of 1 to 2 mm 200 mg fragments thus obtained are weighed very accurately, immersed in a solution of Tyrode and pre-incubated at 37 ° C. for 5 minutes. Next, the immersion solution is added to the antiallergic compound of formula I, suspended in a saline solution. containing 0.5% gum tragacanth, all incubated

  at 37 ° C. for 20 minutes and induced with 10-6 g / ml of ovalbumin.

  After 20 minutes of incubation, the solution is cooled in ice and the amount of histamine released in the medium and remaining in the tissues, by fluorometric assay, is determined in accordance with the protocol of Shore et al (J Pharmacol Exp Ther 127, 182, 1959) The results obtained are listed in the

Table IV below.

  i Compound tested n Intumescence rate Inhibition rate

(%) (%)

Witness 42.58 + 4.10 -

1 29.81 + 7.17 30.0

2 25.00 + 2.77 41.3

TABLE IV

  D. Mesenteric cell degranulation test in the rat Rats are sensitized passively in their abdominal cavity by anti-DNP-As rat serum; 24 hours later, the mesentery of rats is extracted. Then, 100 mg of mesentery is very accurately weighed, which is immersed in the Tyrode solution and pre-incubated at 37 ° C. for 5 minutes. Then, the resulting immersion solution is added. the antiallergic compound of formula (I) suspended in a saline solution containing 0.5% gum tragacanth, the whole being incubated at 37 ° C. for 20 minutes and then induced with 5 × 10 -6 g / ml of DNP-5. After 20 minutes of incubation, the solution is cooled in ice and the mesentery thus treated is colored using formalin (10% of formaldehyde) and 0.1% of a solution of toluidine blue containing 0.1. % of acetic acid, treated with ethanol and xylene and then studied on the plandeladradranulation by mirror inspection (x4,400) The results obtained are

  listed in Table V below.

  Test compound N O Inhibition rate (%) (sodium salt) 4 Conc: 10 g / ml Conc: 105 g / ml

1 83.9 9.2

92.2 83.4

TABLE V

  Compound Conc Rate Rate Tested N O (g / mt) inhibition degranulation Control 97,11 + 0,67

10.4 71.45 + 5.85 22.4

2 10-4 74.96 + 2.91 18.6

  E Acute Toxicity Test The compounds of formula (I) to be tested are each suspended in a saline solution containing 0.5% gum tragacanth, then administered orally to a group of 6 mice of strain dd Y, each mouse weighing 20 to 25 g Lethal doses 50 (LD 50) are calculated from the number of deaths

  mice for three weeks after administration.

  The results obtained are listed in Table VI below.

TABLE VI

  Test compound no LD 50 values (mg / kg)

1> 2000

2> 2000

  The compounds of formula (I) according to the invention have never been described as a drug and it is the Applicant who found that these compounds have a remarkable pharmacological action and a remarkable safety of use, as is apparent from the results. Finally, these compounds are particularly useful drugs as an antiallergic agent. The present invention will be better understood in the light of the following examples which illustrate the preparation of the antiallergic compositions containing the compounds of formula (I) as an active ingredient. In these examples, all the parts

  are by weight unless otherwise stated.

EXAMPLE 1

  100 parts of trans-n-butyl-4-cyclohexane carboxylic acid constituting the active ingredient, 70 parts of granular lactose, 30 parts of corn starch (Japanese pharmacopoeia), 40 parts of crystalline cellulose (Japanese pharmacopoeia) and 1.2 parts of part of magnesium stearate (Japanese pharmacopoeia) are mixed in a multipurpose mixer

  of the Shinagawa type, which results in an anti-

  allergic The latter is introduced into rigid capsules n O 2 to obtain capsules each containing 100 mg of active ingredient The active principle contained in these capsules exhibits remarkable anti-allergic actions as it is apparent

  experiments above developed.

EXAMPLE 2

  41.9 parts of trans-n-pentyl-4-cyclohexane carboxylic acid constituting the active ingredient, 40.8 parts of lactose, 15.7 parts of potato starch and 1.6 parts of hydroxypropylcellulose are mixed in The resultant mixture is pelletized in a pelletizing machine of the extrusion type, after which the pellets obtained are mixed with 50% ethanol and kneaded. Dried, pulverized and granulated to 95.5 parts of granule thus obtained, 4 parts of sodium alginate and 0.5 part of magnesium stearate are added, the whole is mixed in said mixer, resulting in a product. that we turn into tablets containing

  each 40 mg of trans-n-pentyl-4-cyclohexane carboxylic acid.

  These tablets are given to an asthmatic patient; patients treated in this way find a remarkable improvement in their subjective symptoms. There is also an improvement in

objective medical.

  As is clear from the experiment and the examples above, the active principle of the anti-allergic compositions according to the invention, exhibits inhibitory actions on homologous passive cutaneous anaphylaxis (homologous PCA), on degranulation of mesenteric cells; in the rat and on

  histamine release in guinea pig lung fragments.

  This active ingredient is, therefore, a useful drug for the prophylaxis and treatment of allergic diseases and can be used, in particular, for diseases

  allergic diseases such as bronchial asthma, rhinitis

  allergic dermatitis, contact dermatitis, gastrointestinal allergy and anaphylaxis In addition, it is thought that this active ingredient exhibits an anti-complementary action due to its actioninhibitria on reverse cutaneous anaphylaxis (Anglo-Saxon abbreviation: RCA). Finally it is also useful as a medicine for prophylaxis

  and the treatment of cytolysis-like diseases, such as

  allergic hemolytic disease, hypoleucocytosis, thrombocytopenia

  and other hematological diseases, as well as for the prophylaxis and treatment of angio-

  as rheumatism, allergic nephritis and angiitis.

1 1

Claims (2)

  Antiallergic composition, characterized in that it comprises, as active principle, a compound represented by the general formula: R   wherein R is n-butyl or n-pentye.   Antiallergic composition according to claim 1, characterized in that the active ingredient is associated   to a pharmaceutically acceptable carrier.