FR2485532A1 - BENZOTHIAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC COMPOSITION CONTAINING SAME - Google Patents

Abstract

THE SUBJECT OF THE PRESENT INVENTION IS N- (6-HALO-2-PYRIDYL) -3,4 - DIHYDRO-2-METHYL-4-OXO-2H-1,2-BENZOTHIAZINE-3-CARBOXAMIDE 1,1-DIOXIDES WHICH ARE NEW BENZOTHIAZINE DERIVATIVES. THESE COMPOUNDS ARE CHARACTERIZED BY A LOW DEGREE OF TOXICITY, A LOW INCIDENCE OF GASTRIC DISORDERS, AND ARE USED AS ANTI-INFLAMMATORY AGENTS.

Description

The present invention relates to new derivatives

  benzothiazine, a process for their preparation, and pharmaceutical compositions (especially

  anti-inflammatory compositions) containing them.

  In the past, products such as acetyl salicylic acid, fenoprofen, etc. were used as

  anti-inflammatory, analgesic and antipyretic agents.

  More recently, there has been a widespread use of

  products such as indomethacin, diclofenac, etc.

  because of their high anti-inflammatory activity. always

  However, these compounds have disadvantages, in particular

  a high degree of toxicity, a high incidence of

  of gastric disturbances, short-term action, etc.

  That's why products such as Piroxicam

  / 3,4-dihydro-2-methyl-4-oxo-N- (2-pyridyl) -2H-l, 2-benzo

  thiazine-3-carboxamide 1,1-dioxide) and Sudoxicam / 3,4-

  dihydro-2-methyl-4-oxo-N- (2-thiazolyl) -2H-l, 2-benzothia-

  zine-3-carboxamide 1,1-dioxide) have been developed as long-acting anti-inflammatory agents of the benzothiazine series (U.S. Patent 3,591,584). Although these

  compounds exhibit anti-inflammatory activity,

  long-term health, their high degree of toxicity and

  if the high incidence rate of gastric disturbances do not differ significantly from those of indomethacin and

diclofenac.

  Has also been developed (Japanese Patent

  29373/1972), as an anti-inflammatory agent, a

  Isoxicam or 3,4-dihydro-2-methyl-N- (5-methyl)

  3-isoxazolyl) -4-oxo-2H-1,2-benzothiazine-3-carboxamide

  1,1-dioxyde7. This compound has an isoxazole structure

  that, so that its degree of toxicity and incidence of gastric disorders are relatively low. However, its anti-inflammatory activity is less than that of

Piroxicam and Sudoxicam.

  The present invention aims to provide derivatives

  benzothiazine characterized by a low degree of toxicity and a low incidence of gastric disturbances, as well as a potent anti-inflammatory activity and

long term.

  The present invention relates to a N- (6-haio-2-

  pyridyl) -3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine

  3-carboxamide 1,1-dioxide (hereinafter referred to as "compound n1") having the formula: OH 0N (1) wherein the benzothiazine ring is, for convenience, represented as enol with a hydroxyl group in position 4 but actually has a keto-enol tautomerism, and X represents a halogen atom,

  in particular a chlorine or fluorine atom.

  Compound No. 1 defined above is usable as

anti-inflammatory agent.

  Compound No. 1 can be prepared by heating

  dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate methyl 1,1-dioxide (known compound, described in J. Med Chem., 14, 1171, 1971) and 2-amino- 6-halopyridine in xylene, in order to condense them. It is preferable to carry out this reaction using reagents in a molar ratio of 1/1 or using a slight excess of 2-amino-64alopyridine. Usually the temperature of

  reaction is of the order of 100 to 1500C and the reaction time

  is 2 to 30 hours. Once the reaction is complete, the reaction mixture is cooled to cause precipitation and crystallization of the desired product. This product is separated, for example by filtration, and then washed with xylene, an alcohol, chloroform, etc. to obtain very pure crystals. The structure of

  product sought can be confirmed by basic analysis.

re, NMR spectroscopy, etc.

  As representative examples of compounds n 1,

  tera: ie N- (6-chloro-2-pyridyl) -3,4-dihydro-2-methyl-4-acyl

  2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (hereinafter referred to as

  Compound No. 1-1) and N- (6-fluoro-2-pyridyl) -3,4-dihydro-

  2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide 1,1-

  dioxide (hereinafter referred to as compound 1-2). In terms of anti-inflammatory activity, duration, incidence of gastric disturbances and toxicity (LD50), these compounds

  were evaluated as described in Examples 3 to 6 below.

  after. The results thus obtained are summarized in Table 1, to allow a comparison with drugs

  such as Piroxicam, Sudoxicam and Isoxi-

  cam, with classic anti-inflammatory agents like

  indomethacin and diclofenac, as well as

  its well-known analogues such as N- (5-chloro-2-pyridyl) -

  3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide

  mide 1,1-dioxide (hereinafter referred to as 5-chloro compound

  ] 2-pyridyl) and N- (6-methyl-2-pyridyl) -3,4-dihydro-2-

  methyl-4-oxo-2H-benzothiazine-3-carboxamide 1,1-dioxide

  (hereinafter referred to as 6-methyl-2-pyridyl compound).

TABLE 1

  Activity! Disturbances Index Toxicity Margin of anti-infam4 gastro-therapeutical safety mat tical Q 50 DL 50, 5 Compounds tested IDU 50 0 5

DE 50/50 50

  (mg / kg) (mg / kg) (mg / kg) Compound 6 following 1Com1 | 6.5 | 200 30.8 4d000 615 following V: No. 1-1

7.5 1 297 39., 6> 5.00> 667

  No. 1-2 Compounds Piroxicam 1t, 75 8, 2 4,7 490,280 Sudoxicam5,11,8 2,800 3,500 98 Isoxicam 15,5 250 16,1 5,000 322 Indono-mi 4,6n 5,4 1 , 2 17 3.7 m'hacine

Diclo-

  discloses 5-chloro-2-pyridyl compound 6-methyl-4; 5 51 1 '1 1 2-pyridyl! c When this compound is administered orally at a dose of 6.5 mg / kg, the rate of edema suppression

  is very low at 18.9% (see Table 2). It's for-

  which one did not continue the tests with this compound.

  è This value is reported in Pharmacometrics, 6 (6),

1285 (1972).

  This value is reported in Folia Pharmacologica

Japonica, 69, 319 (1973).

  It follows from the results reported in Table 1 that

  benzothiazine derivatives comprising the following compounds:

  In the present invention (compounds 1-1 and 1-2), Piroxicam, Sudoxicam and Isoxicam are all superior.

  indomethacin and diclofenac from indi-

  this therapeutic and safety margin. Among other things,

  The therapeutic range and the safety margin of the compounds 1-1 and 1-2 are remarkably high. It follows that it is considered that the clinical use of the compounds 1-1 and 1-2 has very little risk of causing side effects (i.e. gastric disturbances), such as

  this is often the case after administration of anti-

  non-steroidal inflammatory drugs. In addition, the compounds

  1-1 and 1-2 show an excellent duration of their

  anti-inflammatory, as shown in Table 3

given in example 4.

  It goes without saying from the foregoing that the compounds

  n 1-1 and 1-2 exhibit not only an anti-

  inflammatory and long-lasting, but also

a very high degree of safety.

  Depending on the type of symptoms and their sites of

  cation, compounds 1-1 and 1-2 may be administered

  in various forms: for example in the form of pre-

  oral formulations, such as:

  award-winning capsules, powders, granules, etc .; suppositories;

  liquid preparations; ointments; injection solutions

  tables for intravenous, intramuscular and other injections; etc. However, it is preferable to administer them in the form of oral absorption preparations and suppositories. The dosage, in adults,

  is from 1 to 50 mg and preferably from 5 to 20 mg of

  active ingredient. Usually, it is sufficient to administer the

  Compounds No. 1-1 or 1-2 once a day.

  The pharmaceutical compositions according to the present

  invention contain the active ingredient at a concentration

  about 10 to 95%, and preferably 15 to 90%.

  They can be prepared by any standard technique

  well known, for example by mixing, transforming

  granules, coating with sugar, dissolving

  and lyophilization. For example, a composi-

  pharmaceutical composition to be administered orally in

  containing the active ingredient with a solid carrier, then optionally adding the desirable additives. In

  In particular, sugars and cellulose derivatives are used.

  calcium phosphate, etc. as a vehicle; and binders, disintegrating agents (such as starch), flow regulators, lubricants

  etc. as additives. In addition, depending on the type of preparation

  Any suitable substances may be incorporated into the pharmaceutical compositions of the present invention. The following non-limiting examples are given in

  Illustrative of the present invention.

Example 1

  Preparation of N- (6-chloro-2-pyridyl) -3,4-dihydro-2-

  methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide 1,1-

  dioxide (1) Synthesis of 2-amino-6-chloropyridine In a 1-liter autoclave 100.6 g are introduced

  (0.68 moles) of 2,6-dichloropyridine and 500 ml of a solution

  29% ammonia. The resulting mixture is brought to

  1900C and stirred for 5.5 hours. We abandon the

  lange overnight to cool; the resulting precipitate is separated by filtration and washed with ice water. The precipitate is then dissolved in 500 ml of dichloromethane and the resulting solution is washed with 400 ml of water. The dichloromethane layer is dried on

  anhydrous sodium sulphate, then concentrated to dryness,

  62.8 g of pale yellow crystals having a

  73 C melting, with a yield of 71.8%. Chromatography

  Thin layer graphs (TLC) (with a solvent system consisting of a 25/1 mixture of CH 2 Cl 2 and EtOH) gives

an Rf of 0.36.

  (2) Synthesis of N- (6-chloro-2-pyridyl) -3,4-dihydro-2-

  methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide

  A mixture of 5.38 g (0.02 mol) of

  dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate 1,1-

  methyl dioxide, 3.86 g (0.03 mol) of 2-amino-6-chloro

  pyridine, and 100 ml of refluxing kylene for 7 hours during which the methanol formed by this reaction is removed continuously by distillation. We give up

  mix overnight, to cool. We separated

  the resulting precipitate, by filtration, it is washed with

  stirring in a 1: 1 mixture of methanol and chloroform

  warm, it is collected by filtration and dried, thus obtaining 4, 15 g of a final product having a point of

  amalgamation of 269-270 C (decomp.), with a yield of 56.7%.

  Elemental analysis: for C15H12ClN3O4S (M = 365.791) CH Cl NS Calcd: 49.25 3.31 9.69 11.49 8.46 Found: 49.36 3.38 9.89 11.66 8.66 NMR Spectrum (DMSO-d6, 100 C) 2.84 (3H, s, N-CH3) 7.34 and 8.0 (7H, m, C6H4 and C5H3N) 9.3 (1H, broad NH)

, 34 (1H, broad OH).

  IR spectrum (KBr): 3305, 1638, 1580, 1530, 1442, 1412, 1360, -1 1302, 1190, 1170, 1052, 842, 750 cm

Example 2

  Preparation of N- (6-fluoro-2-pyridyl) -3,4-dihydro-2-methyl-

  4-oxo-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (1) Synthesis of 2-amino-6-fluoropyridine

  4.75 g of 2,6-difluoride are introduced into an autoclave.

  oropyridine and 48 ml ammonia 29%. We wear the

  resulting mixture at 150 ° C. and stirred for 45 minutes.

  The mixture is left overnight to

  froidisse. The resulting precipitate is filtered off and washed with ice water. Then we dissolve

  precipitate in 50 ml of dichloromethane and wash the

  the resulting solution with 40 ml of water. The dichloromethane layer is dried over anhydrous sodium sulphate,

  and concentrated to dryness. The resulting residue is recrystallized

  in a mixture of chloroform and petroleum ether, obtained

  thus 3.4 g of crystals having a melting point of

56-58 C, with a yield of 75%.

  (2) Synthesis of N- (6-fluoro-2-pyridyl) -3,4-dihydro-2-

  methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide

  A mixture of 7.68 g (0.0285 mol) of

  dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate 1,1-

  methyl dioxide, 4.8 g (0.0428 mol) of 2-amino-6-fluoro

  ropyridine, and 29 ml of xylene, under reflux, for 17 hours.

  in which the methanol formed by the reaction is removed continuously by distillation. We give up

  overnight to cool and separate

  The resulting precipitate is filtered off. The filtrate is concentrated and cooled, thus obtaining a precipitate

  supplemented by the first and washed with chlorine

  hot roform. 7.2 g of crystals having a melting point of 246 ° -248 ° C. (decomp.) Are thus obtained with a yield of

72.3%.

  Elemental analysis: for C15H2FN30S (M = 349.35)

12N304S

C H F N S

  Calculated: 51.55 3.46 5.44 12.03 9.18 Found: 51.69 3.23 5.55 12.29 9.14

  NMR spectrum (DMSO-d6) δ = 2.87 (3H, s, N-CH3); 6,92-

  7.1 and 7.85-8.2 (7H, m, C6H4 and C5H3N); 10.70 (1H,

wide OH).

Example 3

  The anti-inflammatory activity was evaluated as follows: Male Wistar rats were used in batches of 7. The test compound is suspended in 0.2% carboxymethylcellulose solution and administered at the same dose.

  0.5 ml / 100 g body weight. One hour after the adminis-

  administration of the test compound, 0.1 ml of a

  carrageenan solution at 1% (which causes inflammation

  subcutaneously, in the plant of Lapatte pos-

  right side of each rat. Three hours after the injection

  carrageenin, each rat is sacrificed with the aid of

  The limbs of both hind limbs are amputated

  the ankle and weigh them in order to determine the

  difference in weight between the two legs. It is then estimated

  the power of the test compound to suppress the oed-

  caused by carrageenan by comparing the difference between the weight of the legs of the group tested and the weight of the legs of a control group (consisting of rats to which only the solvent was administered). The suppression rate of the edema is calculated according to the following equation: Suppression rate of edema (%) =

  (Difference (g) between the weights of the legs of the control group) - (Dif-

  (Difference (g) between the weights of the difference (g) between the weight of the legs of the lot tested) x 100 legs of the control lot)

  The results thus obtained are reported in Table 2 below.

  after. EXAMPLE 4 The duration of the antiinflammatory activity is studied as follows: Using the DE50 values determined at

  Example 3 investigates the duration of the anti-inflammatory activity.

  matemaking by varying the premedication time. Premedication time is defined as the elapsed time

  between the administration of a test compound and the injection

  carrageenan. The tests are carried out in substance as described in Example 3. The results obtained are

reported in Table 3 below.

  6 'Z8 T' LZ 6 '81 ú' 69: 81S Z '6Z ú ú ú ú ú L L L L L L L L 69 69 69 69 69 69 69 69 ú L 69 69 69 69 69................. ú'glh 6 9Z S'9 SL 'S 9

O * '01

  SO, Z SZ; I 0: .0u oOzS O0'0I O '51 OS 's zZ

S The úC

O; '01 O'S S: Z SZ'I S9 'Z SZ' 1

Sú39 O0

  a! Ap! aXLd -: - IXm addl ap asoduioDi ú I adil ap asodumOD! to Guip a; oF a honeyDIXO sú1 ú1 i OZ eD TxopnI5 aS

EEDIXOI 1 &

9'99 0'91

9'1S O '8

  O'ZúS 01O and O'O OZ Z-I ON 9soduiOaJ

O 'HE O' 9

  9 0S O is 9 úbOS (O 'ss e9 t' 61 OZ 1-1 'oo ps dd = Dl aDtuQppij ap (Od asa ZO, ap uo! Sseiddns to uoIssaiddns </ U 2uVsinpo.ld eso (ap xnv% ieoI Z nleIq-el O 'S 9' bz S SZT

TABLE 3

  Suppression rate of edema (%) in rats at the end of various premedication times

  1 hr. 3 hrs! 6 hrs. 12 hrs. 24 hrs.148 hrs.

  . ## EQU1 ##, ## STR1 ## where: ## STR1 ## 12. 6 43.81 207 3.4 s4o. -2 56.6 54.8 9 43.2, I Pi roxican 57.6 55.3 40.0 38.8 15.3 1.7 Sudoxicamr 49.8 52.1 39.5 31.6 10.4 -2.4 Isoxi-cam 54 , 2 2 | 45 8 36 3 19.5 1.1 Indomethacin 49.4 57.6 29.4 18.8 -3.5 Diclofenac 45. 9 24.7 17.6 11.8 -1.2

Example 5

  The incidence of gastric disturbances in rats was evaluated as follows: In batches of 5-7, male Wistar rats 8 weeks old were used. After making them fast

  for 18 hours or more, the test compound is administered

  ter oral. Six hours later, we sacrificed each

  than rat by decapitation. We take the stomach, introduce it

  10 ml of physiological saline, and then

  5% formalin. After about 10 minutes, the

  tomac along the large curvature and the presence or absence of gastric

  especially if there is erosion or not). In accordance with

  In the Litchfield-Wilcoxon test pan, the erosive dose was calculated on an all-urian basis in% of the animals tested (DU50). The results obtained are

reported in Table 4.

TABLE 4

Example 6

  Acute toxicity is studied as follows: Male ddY mice are used in batches of 5. The test compound is suspended in a 0.2% carboxymethyl cellulose solution and administered orally at a dose of 0.1 ml / 10 g body weight. Then we put

  animals under observation for 7 days. We calculate the

  their LD50 based on the last day mortality.

  The results obtained are reported in Table 5.

TABLE 5

Compound no] Compound n iroxicam

________________ L

  Number of deaths / Total number of animals tested 0/5 2/5 3/5 0/5 0/5 0/5 0/5 1/5 1/5 4/5 / 5 Test compound DU50 (mg / kg, po) Compound n 1-1 200 Compound n 1-2 297 Piroxicam 8.2 Sudoxicam 11.8 Isoxicam 250 Indomethacin 5.4 Diclofenac 9.2 Compound of type 6-methyl-2-pyridyl 5.1 LD50 (mg / kg) 4.000 5.000 I TABLE 5 (cont'd) Tested Cose Dose No mcrts / LD50 Idm / g P0) Total Nobore (mg / kg r animals tested (mg / kg, po) Sudoxicam 200 0 / 5,500

400 2/5

l & 800 4/5

1,000 5/5

Isoxicam 3.000 0/5 5.000

I4.000 1/5

t ________________ 5.000 3/5 1- /

Example 7

  Tablets containing the compound n 1-1 having the following composition are prepared: Compound n 1-1 10 mg Corn starch 270 mg Polyvinyl pyrrolidone 15 mg Magnesium stearate 5 mg Using a tablet-making apparatus, the tablets are mixed together. ingredients above and compresses them into one tablet.

Example 8

  Capsules containing compound 1-1, having the following composition are prepared: Compound n 1-1 10 mg Corn starch 230 mg Lactose 50 mg Magnesium stearate 10 mg

  The above ingredients are mixed and then

  closes in a hard gelatin capsule.

Example 9

  Suppositories containing n 1-1 compound are prepared by placing 20 mg of compound n 1-1 as a

  fine powder, suspended in 5 ml of O.D.O. (triglycé-

  medium chain long chain fatty acid wrinkles, products

  by Nisshin Seiyu Co.) and the resultant suspension is

  aunt in a soft gelatin capsule.

Claims (5)

  1. A compound selected from N- (6-halo-2-pyridyl) -3,4-   dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides. 2. The compound of claim 1 which is   N- (6-chloro-2-pyridyl) -3,4-dihydro-2-methyl-4-oxo-2H-1,2-   benzothiazine-3-carboxamide 1,1-dioxide.   3. A compound according to claim 1 which is   N- (6-fluoro-2-pyridyl) -3,4-dihydro-2-methyl-4-oxo-2H-1,2-   benzothiazine-3-carboxamide 1,1-dioxide.   4. Pharmaceutical composition having in particular anti-inflammatory properties, characterized in that it contains as active ingredient a compound according to one   any of the preceding claims, in combination   with a pharmaceutically acceptable vehicle.   5. Process for preparing N- (6-halo-2-pyridyl) -   3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide   mide 1, 1-dioxides, characterized in that a 3,4-dihydric   Dro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate 1,1-   dioxide with a 2-amino-6-halopyridine.