FR2511683A1 - Carboxy-piperazino pyrido-benzothiazepine(s) - having anti:histamine and anti:anaphylactic activity - Google Patents

Abstract

Carboxy piperazino pyrido benzothiazepines of formula (I) and their acid addn. salts are new. (In (I), X= O or S; R= H, alkyl, alkoxy or phenoxy. (I) are antihistamines and antianaphylactic agents, useful for the treatment of allergies and asthma. These cpds. are not orexigenic. (I) are prepd. by reacting cpd. of formula (II) and (III). This reaction is pref. effected in an aromatic solvent such as benzene or toluene in the presence of a base such as triethylamine or the corresp. piperazine.

Description

New derivatives of pyridotZ, 3-bzbenzothiazepine (1,5) -substituted in 5 by a carboxypiperazine their method of preparation. their application in therapeutics.

The present invention relates to novel 5-substituted pyridor2,3-b] benzothiazepine derivatives (1,5) and having the general formula (I). It also relates to the application of said derivatives and their non-toxic acid addition salts in therapy.

In formula (I)
X represents oxygen or sulfur
- R is hydrogen, an alkyl, alkoxy or phdnoxy radical, preferably R represents the ethoxy group.

 The compounds of formula (I) are synthesized by the action of a substituted piperazine of general formula (II) on the chlorinated derivative of formula (III).

The reaction is carried out in an aromatic solvent such as benzene or toluene in the presence of a base such as, for example, triethylamine or the corresponding piperazine.

 (In formula (II), X and R have the meaning given above).

 The acid addition salts of the compounds of formula (I) can be obtained by reaction with a mineral or organic acid according to a method known per se. Among the acids that can be used for this purpose, mention may be made of hydrochloric acid, methanesulphonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, cinnamic acid, aspartic acid, lactic acid, ascorbic acid, benzoic acid, and the like.

 Some of the new compounds according to the invention are endowed with valuable pharmacological properties and may be useful therapeutically as antihistamine and antianaphylactic.

These products are not addictive.

 In combination with a physiologically acceptable excipient, the compounds of formula (I) or a non-toxic acid addition salt thereof may be used for the treatment of allergies and asthma.

 The following examples are given to illustrate the invention without limiting its scope. The table below gives the structural formula of certain exemplified compounds.

EXAMPLE 1 (700-06) (Carbethoxy-1-piperazinyl-4) -5-pyrido, 3-benzothiazepine (15) (base and dihydrochloride)
formula (I) X = o R = OC2H5 a) Base:
To a solution of 18.5 g of 5-chloro-pyrido [2,3-b] benzothiazepine (1,5) in 75 ml of anhydrous toluene is added dropwise a mixture of 10.5 ml of triethylamine and 11 ml. 8 g of carbethoxy-1 piperazine in solution in 75 ml of anhydrous toluene. The reaction mixture is refluxed for 8 h and then cooled to room temperature. The precipitate of triethylamine hydrochloride is removed by filtration and the toluene phase is concentrated in vacuo. The pasty residue is then taken up in 100 ml of a solution of hydrochloric acid N and the aqueous solution is turned to black.

 After filtration, the acidic aqueous phase is washed with twice 25 ml of ether and then neutralized with a cold solution of ammonia. The basic phase is then extracted with twice 50 ml of chloroform which is dried over magnesium sulphate. After filtration and evaporation of the solvent, 25 g of a crude solid are obtained which, taken up in 150 ml of ether, gives 16.5 g of (4-carbethoxy-4-piperazinyl) pyrido2,3-bbenzothiazepine (1, 5) as yellow-white crystals melting at 140 ° C.

b) Dihydrochloride:
10 g of the previously obtained base are dissolved in dry acetone. Saturated ether is then added in hydrochloric acid to pH 1. The precipitate formed is filtered, washed with acetone and then with ether. 11 g of (carbethoxy-1-piperazinyl-4) -5-pyrido [2,3-b] benzothiazepine (1,5) are thus obtained in the form of yellow crystals melting at 180 ° C.

EXAMPLE 2 (776-01) (Carboxaldehyde-1-piperazinyl-4) -5-pyrido (2,3-b) benzothiazine (1,5)
formula (I) X = OR = H
According to the procedure of Example 1, using 12.3 g of chloro-5-pyrido [2,3-b] benzothiazepine (1,5), 7 ml of triethylamine and 5,7 g of N-carboxaldehyde piperazine, 3.5 g of (1-carboxaldehyde-4-piperazinyl) pyrio [2,3-b] benzothiazepine (1,5) are obtained in the form of white crystals, melting at 159 ° C.

formule (I) X = O R = CH3 (Acétyl-l pipérazinyl-4)-5 pyrido[2,3-benzothiazépine(1,5)
On ajoute sous agitation 2,4 ml de chlorure d'acétyle à une solution benzénique de 8,8 g de (pipérazinyl-l)-5 pyrido[2,3-b] benzothiazépine(1,5) et de 3,3 g de triéthylamine. Ce mélange réactionnel est laissé 2 h à température ambiante puis hydrolysé par 100 ml d'eau. La phase organique est ensuite décantée puis séchée sur sulfate de magnésium. Après évaporation du solvant sous vide, le résidu est repris dans l'éther et donne 5,2 g d'(acétyl-l pipérazinyl-4)-5 pyrido[2,3-b]benzothiazépine(1,5). F. 216" C. EXAMPLE 3 (776-08)

formula (I) X = OR = CH3 (1-acetyl-4-piperazinyl) pyrido [2,3-benzothiazepine (1,5)
2.4 ml of acetyl chloride are added with stirring to a benzene solution of 8.8 g of (1-piperazinyl) pyrido [2,3-b] benzothiazepine (1,5) and 3.3 g. of triethylamine. This reaction mixture is left for 2 hours at room temperature and then hydrolysed with 100 ml of water. The organic phase is then decanted and then dried over magnesium sulfate. After evaporation of the solvent in vacuo, the residue is taken up in ether and gives 5.2 g of (1-acetyl-4-piperazinyl) pyrido [2,3-b] benzothiazepine (1,5). F. 216 ° C.

ANTI-ALLERGIC ACTIVIST
I - PASSIVE CUTANEOUS ANAPHYLAXIS a) Method
A technique derived from that described by MoSA I. Immunology, 1964, 7, 681 which consists in sensitizing batches of 7 to 12 CD strain Charles River rats weighing 180-200 g by four intradermal injections of 0.1 ml of rat antiserum; the antiserum is obtained from animals treated with a mixture of ovalbumin and bordetella pertussis.It is diluted to cause in animals
2 controls, in the presence of the antigen, a cutaneous reaction of at least 100 mm. 72 hours after sensitization, the animals to be studied are administered intravenously or intraperitoneally, and 1 ml per rat (IV) of a solution of 0.25% Evans blue + ovalbumin 5 mg / ml in an aqueous solution. isotonic sodium chloride 9 #. 30 minutes after this last injection, the animals are sacrificed and the surface of each blue spot corresponding to the injection site of antiserum is measured.

 The results are expressed as percentage of decrease of the colored surface. The Di50 is calculated according to Bliss.

 The significance of the results is given by Student's "t" test.

sont pris comme substances de référence au moment des essais rapportés ci-dessous

b) Results
Disodium cromoglycate and the compound (IV) of the formula

are taken as reference substances at the time of the tests reported below

<tb><SEP> Administration <SEP> Intraperitoneal <SEP> Administration
<tb><SEP> intravenous
<tb> Doses <SEP> in <SEP> 700-06 <SEP> 700-01
<tb> mg / kg <SEP> 1 <SEP> Product <SEP> of <SEP> Compound <SEP> IV <SEP> Cromoglycate <SEP>
<tb><SEP> the example <SEP> 1 <SEP> disodium
<tb> 0.15
<tb> 0.25
<tb> 0.31
<tb> 0.5
<tb> 0.625 <SEP> 7 <SEP> ns
<Tb>

<SEP> 1 <SEP> 44 <SEP> *** <SEP>
<tb><SEP> 1.25 <SEP> 19 <SEP> *** <SEP>
<tb><SEP> 2 <SEP> 37 <SEP> *** <SEP> 45 <SEP> iti <SEP>
<tb> 2.5 <SEP> 64 <SEP> 64 * n <SEP>
<tb> 4 <SEP> 64 <SEP> * t * <SEP> 48 <SEP> *** <SEP>
<tb><SEP> 5 <SEP> 73 <SEP> *** <SEP>
<tb><SEP> 8 <SEP> 86 <SEP> *** <SEP> 68 <SEP> * n <SEP>
<tb> 16 <SEP> 69 <SEP>
<tb> 32
<tb> 64
<tb> DA50 <SEP> 2.78 <SEP> l <SEP> 2.5 <SEP> 2.4
<tb> ns not significantly different from controls i significant difference compared to controls p '0.05 ** significant difference compared to controls p <0.01 *** significant difference compared to controls p> 0.01
It - ACUTE TOXICITY
It is sought on batches of 2 male rats of strain OFA (Iffa Credo) weighing 115 to 150 g. The animals receive the products intraperitoneally and the mortality is recorded for 7 days.

 The lethal doses 0 (DLo) and lethal 100 (LD100) are determined at the end of the observation period.

The values obtained for compound 700-06 (example 1) are as follows:
DL = 128 mg / kg
DL100 = 256 mg / kg and for compound IV:
DL = 32 mg / kg
DL100 = 64 mg / kg
III - CONCLUSION
Product 700-06 has a passive skin reaction inhibitory activity equivalent to that of compound IV, but its lower toxicity gives it a better therapeutic index.

 It can therefore be used as a preventive medication for asthma, in the form of tablets or capsules dosed with 1 to 50 mg of injectable solution of 0.5 to 10 mg per ml, aerosol dosed at a rate of 1 to 10 mg by inhalation.

 It will be noted that the product of Example 2 is not very active and that of Example 3 is inactive.

BOARD

Example 1
Example 2

Claims (7)

 R represents H, an alkyl, alkoxy or phenoxy radical, and their acid addition salts.  X represents oxygen or sulfur, and  in which

 1. New compounds, characterized in that they respond to the formula 2. New compounds according to claim 1, characterized in that X represents oxygen. 3. New compounds according to claim 1 or 2, characterized in that R represents the ethoxy group. 4. New compound according to any one of claims 1 to 3, characterized in that it consists of (carbethoxy-1-piperazinyl-4) -5 pyrido (2> 3-b) benzothiazepine (1,5). 5. New drugs, useful in particular as antihistamines and antianaphylactics, characterized in that they contain at least one compound according to any one of claims 1 to 4, excluding the compound wherein R = CH3 and X = 0 simultaneously . 6. New drug according to claim 5, characterized in that it consists of (carbethoxy-1-piperazinyl-4) -5 pyrido [2,3-b] benzothiazepine (1,5). 7. Process for the preparation of the new compounds according to any one of Claims 1 to 4, characterized in that the compounds of formulas (II) and (ICI) are reacted together.

 wherein X and R are as defined in any one of claims 1 to 4 in an aromatic solvent such as benzene or toluene in the presence of a base such as triethylamine, or the corresponding piperazine.