SI8811992A - Process for preparation of 1,1-dioxide amide 6-chlorine-4-hydrohy-2- methyl-n-(2-pyridyl)-2h-thieno-(2,3-e)-1,2-thiazine-3-carboxylic acid enol esters - Google Patents

Abstract

The invention relates to a process for preparing new ones 6-chloro-4-hydroxy-2-methyl-N- (2-pyridyl) -2H-thieno (2,3-e) -1,2-thiazine-3-one-liter 1,1-dioxide amide carboxyl of an acid (chlorothenoxicam) of formula I CH3 ---- CH — O ■ C — ΟΙ o fl in which R is (C 1 -C 8 alkyl), (C 5 -C 7) cycloalkyl, or benzyl, with the metabolism of the chlorothenoxicam of formula II in which M + is an alkali or alkaline earth cation or tetraalkylammonium, with a compound of formula III X I CH .---- Ctt-0 — C — 0 — fl il o in which R has the above meaning and X represents halogen, v reaction-inert organic solvent. New compounds have anti-inflammatory activity and are suitable for treatment of rheumatism.

Description

CHEMISCH PHARMATEUTISCHE FORSCHUNGSGESELLSCHAFT m.b.H.

Process for the preparation of 1-liter 1,1-dioxide amide 6-chloro-4-hydroxy-2-methyl-N (2-pyridyl) -2H-thieno- (2,3-e) -1,2-thiazine-3-carboxyl acid

Field of the Invention (MPK C 07D 513/04; A 61K 31/54)

The invention is within the scope of the pharmaceutical industry and relates to a process for the preparation of new one-liter 1,1-dioxide amide 6-chloro-4-hydroxy-2-methyl-N- (2-pyridyl) -2H-thieno (2,3-e ) -1,2-Thiazine-3-carboxylic acid of formula I

Cl

I in which R is (C 1 -C 4 -alkyl, (C ₅ -C ₇ ) -cycloalkyl or benzyl, and for use in medicaments having anti-inflammatory effects.

A technical problem

There is a need for new chlorothenoxycam derivatives that do not cause the irritation of the gastrointestinal tract, which penetrate the skin well and which have better pharmacological efficacy than previously known related compounds.

The state of the art

US-PS 4,180,662 describes anti-inflammatory-effective analgesics. Of the substances described in this US-PS, 1,1-dioxide of the amide 6-chloro-4-hydroxy-2-methyl-N- (2-pyridyl) -2H-thieno (2,3-e) proved to be particularly effective -1,2-Thiazine-3-carboxylic acid (chlorothenoxyam). However, this compound can cause its polar and acidic structure in rare cases of gastrointestinal irritation. The topical preparations of this substance have the disadvantage that they penetrate through the skin only unsatisfactorily and paint the colored clothing pieces with their intense yellow color.

EP-PS 0147 177 discloses one-octic oxic. However, the one-liter described in this EP-PS has the disadvantage that the pharmacological activity of these one-liter is less than the activity of non-aether oxicams.

Description of solution to a technical problem with implementation examples

Surprisingly, we have now found that the one-year-olds of the present invention, which are colorless and therefore suitable for topical applications, have a higher pharmacological activity than non-ethereal chlorothenoxicam.

The object of the invention is therefore a process for the preparation of compounds of formula I in which R is (C ₁ -C ₆ -alkyl, (C ₅ -C ₇ ) -cycloalkyl or benzyl, wherein the compounds of formula I are prepared such that the chlorothenoxicam salt of formula II

2a

Of-) o

Kateri in which M ⁺ is an alkali or alkaline earth cation or tetraalkylammonium, is reacted with a compound of formula III

III in which R has the above meaning and X represents halogen, in a reaction-inert polar aprotic solvent.

The term (C ₁ -C ₆ ) -alkyl used herein denotes unbranched or branched saturated hydrocarbon residues of 1 to 6 carbon atoms, such as e.g. methyl, ethyl, isopropyl, tert-butyl, hexyl. By halogen is meant chlorine, bromine or iodine.

A preferred compound is 1,1-dioxide amide 6-chloro-4- (1- (ethoxycarbonyloxy) ethoxy) -2-methyl-N- (2-pyridyl) -2H-thieno (2,3-e) -1. 2-Thiazine-3-carboxylic acids.

r

The necessary salts of chlortenoxicam can be used in isolation, but better prepared in situ by the addition of at least one equivalent of a strong base such as e.g. alkali hydrides or alkali carbonates to the reaction solution.

The reaction of a compound of formula II with a compound of formula III is carried out in a reaction-inert, polar, aprotic, anhydrous solvent, such as e.g. DMF, DMSO, acetone, 2-butanone, etc. The reaction temperature is not critical and lies between the room temperature and the boiling point of the solvent used. The duration of the reaction depends on the reaction temperature and the leaving group X; The reaction is generally accelerated by the addition of sodium iodide (Finckelstein reaction), using NaJ in up to three times the excess with respect to the alkylating agent.

Preferred reaction conditions are the metabolism of chlorotenoxycam with the compounds of formula III in acetone as solvent and sodium or potassium carbonate as a base in 3-4 times excess at reflux temperature and NaJ as the reaction accelerator, using per mole of alkylating agent

1.5 to 2 moles of NaJ.

Chlorthenoxicam can be prepared according to US-PS 4,180,662. The compounds of formula III are either commercially available or can be prepared according to H.Mullerjera, J.Liebigs Ann. Chem. 258, 50 (1890) or according to EP-PS 0147 177.

The novel compounds of formula I exhibit excellent anti-inflammatory activity in in vitro models.

Based on this pharmacological characteristic, new compounds may be used alone or in admixture with other active ingredients in the form of conventional galenic preparations to inhibit inflammation and relieve pain in diseases such as rheumatism.

The anti-inflammatory property can be determined by generally known standard methods, such as e.g. with carrageenan (carrageenan) induced swelling of the paw rat rat. In this test (Case 2) _? in which we compare the anti-inflammatory activity of chlorotenoxicam, one liter of chlorotenoxicam, viz.

6-Chloro-4- (1- (ethoxycarbonyloxy) ethoxy) -2 methyl-N- (2-pyridyl) -2H-thieno (2,3-e) -1,2-thiazine-3 1,1-dioxide amide 2-methyl-N- (2-pyridyl) -4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid (1-carboxylic acid, piroxicam (1,1-dioxide) amide) and one-liter piroxicam, namely 1,1 4 - ((1e Toxicarbonyl loxy) e toxins) -2-methyl-N- (2-pyridyl) -2H-1,2-benzo-thiazine-3-carboxylic acid amide dioxide has been shown to yield at given the conditions of the attempt to achieve an 80% inhibition of inflammation with only one liter of chlorothenoxicam. From the value of 50% inhibition of inflammation, one can conclude that one liter of chlorothenoxicam is almost twice as effective as chlorothenoxicam, whereas one year of piroxicam is significantly less effective than piroxicam. This is followed by the following sequence of impaired anti-inflammatory potency: one-liter of chlorothenoxicam / chlorotenoxicam / piroxicam / one-liter of piroxicam.

The compounds of formula I are intended for use in mammals, especially humans, and can be administered in a conventional manner, such as e.g. orally or parenterally. They are preferably administered orally or topically, with a daily dose of about 0.5 to 100 mg, preferably 1.0 to 10 mg, when administered orally. Depending on the general condition and age of the patient, the appropriate substance of Formula I, the type of disease and the type of formulation, the attending physician may also prescribe higher or lower doses. For topical administration, the concentration of the compound of formula I is between 0.01 and 3%.

The compounds of formula I may be administered alone or in association with other pharmaceutically active substances, with a content of compounds of formula I ranging from 0.1 to 99%. In general, pharmaceutically active compounds are present in admixture with suitable inert excipients and / or carriers or diluents, such as e.g. pharmaceutically acceptable solvents, gelatin, gum arabicum, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycol, petroleum jelly and the like.

The pharmaceutical preparations may be in solid form, e.g. as tablets, dragees, suppositories, capsules, etc., in semi-solid form, e.g. as ointments or gel, or in liquid form, e.g. as solutions, suspensions or emulsions. In the present case, they are sterilized and contain excipients such as preservative stabilizing or emulsifying agents, salts for changing the osmotic pressure and the like.

In particular, pharmaceutical compositions may contain the compounds of the invention in combination with other therapeutically valuable substances. With these, the compounds of the invention can be formulated into combination preparations, e.g. together with the excipients and / or carriers or diluents mentioned above

EXAMPLE 1

6-Chloro-4- (1-ethoxycarbonyloxy) ethoxy) -2-methyl-N- (2-pyridyl) -2H-thieno (2,3-e) -1,2-thiazine-3-carboxyl 1,1-dioxide amide acid g (26.9 mmol) of 6-chloro-4-hydroxy-2-methyl-N- (2-pyridyl) -2H-thieno- (2,3-θ) -1,2- 1,1-dioxide amide of thiazine-3-carboxylic acid, 9.29 g (99.5 mmol) of potassium carbonate and 15.1 g (99.5 mmol) of 1-chloroethylethylcarbonate were heated in reflux for 150 ml in acetone for 20 hours. 24.5 g (163.3 mmol) of sodium iodide are then added and heated to reflux for 5 hours. The extracted sodium chloride was then filtered off, the filtrate was evaporated and partitioned between 100 ml of methylene chloride and 100 ml of saturated sodium bicarbonate solution. The phases were separated and the organic phase was washed with 100 ml of water and 20 ml of 3% sodium bisulfite solution. Dry over sodium sulfate, filter and evaporate. The resulting oily crude product (17.5 g) was filtered through silica gel (100 g Kieselgel 60, granularity 0.04 - 0.063 mm, eluent: methylene chloride: ethyl acetate = 9: 1). 10.1 g of light orange crystals are obtained.

They were dissolved in 17 ml of dioxane at boiling point, 0.6 g of activated charcoal was added to the solution and then hot filtered. Cool and add 40 ml of diethyl ether. The separated colorless crystals were filtered off with suction, washed with ether and dried at 50 ° C / 1 mbar.

Yield: 6.3 g of colorless crystals (48% of theory). Mp: 148 ° C (decomposition).

1 H-NMR (CDCl ₃ ):

delta (ppm): 8.9 (broad 1H; -NH-); 8.3 (m; 2H; Py-H); 7.8 (m; 1H; Py-H); 7.2 (s;

IH; Th-H); 7.1 (m; 1H; Py-H); 6.5 (q; 1H; O-CH-O); 4.1 (q; 2H; - CH ₂ -); 3.2 (s; 3H; N-CH 3); 1.7 (d; 3H; -CH-CH 3); 1.2 (t; 3H; -CH ₂ -CH ₃ ).

^1? C-NMR (CDC1 _3):

delta (ppm); 157.9; 153.1; 150.5; 147.9; 142.1; 137.9; 135.9; 135.5; 134.9; 126.6; 121.1; 120.1; 113.9; 100.1; 64.4; 36.7; 19.9; 13.7.

EXAMPLE 2

Test with carrageenan induced swelling of the rat paw

The anti-inflammatory effect of the test substances was tested by their inhibitory effect on carrageenan-induced swelling of the paw rat.

The following were used as test substances:

chlorotenoxycam (1,1-dioxide amide 6-chloro-4-hydroxy-2-methylN- (2-pyridyl) -2H-thieno (2,3-e) -1,2-thiazine-3-carboxylic acid) 6-Chloro-4- (1- (ethoxycarbonyloxy) ethoxy) -2-methyl-N- (2-pyridyl) -2H-thieno (2,3-θ) 1,2-thiazine (1,1-dioxide amide -3-carboxylic acid piroxicam (1,1-dioxide amide 2-methyl-N- (2-pyridyl) -4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid) enol ether piroxicam (1,1-dioxide 4- (1- (Ethoxycarbonyloxy) ethoxy) -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxylic acid amide)

Before the start of the experiment, the volume of the right hind paw rat was plethysometrically determined and recorded in ml of water displacement.

The test substances were administered orally with a pharyngeal probe as a suspension in 0.5% carboxymethylcellulose. The dosage was 0.3 / 1.0 / 3.0 and 10 mg / kg body weight. On each substance and dose, respectively. control tested 8 animals. One hour later, an injection of 0.05 ml of a 2% solution of lambda carrageenan in 0.9% NaCl was initiated into the right hind paws of the experimental animals. 3 and 4 hours after triggering the inflammation, further plethysometric determination of the volume of the right hind paw rats was performed. The inhibition of inflammation is given as a percentage. From these values, 80% and 50% of IHD (Inhibition Dosis) are calculated. (80% of IHD delivers that dose in mg / kg body weight that is able to inhibit 80% inflammation).

80% IHD values:

substance one-year chlorothenoxam chlorothenoxam piroxicam one-year piroxicam n.d .: not available

3 hrs karaginanu (mg / kg) 4 hrs karaginanu (mg / kg) geometric medium value (mg / kg) 3.01 3.03 3.02 n .d. n.d. n.d. n .d. n.d. n .d. n .d. n .d. n .d.

- 9 Values of 50% IHD:

substance 3 hrs karaginanu (mg / kg) 4 hrs karaginanu (mg / kg) geometric medium value (mg / kg) one liter of chlorotenoxicam 0.23 0.36 0.29 chlorotenoxicam 0.35 0.60 0.46 piroxicam 3.88 5.06 4,43 one liter of piroxicam v.k. 10 v.k.10 v .k.10 vk: more than

EXAMPLE 3

Preparations of one-liter batch of chlorothenoxycam gel In a FRYMA process plant, 8 g of 1,1-dioxide amide 6-chloro-4- (1- (ethoxycarbonyloxy) ethoxy) -2-methyl-N- (2pyridyl) -2H-thieno (2,3 -e) -1,2-Thiazine-3-carboxylic acid in 4717 g ethanol and 2082 g water. Into this solution, 167 g of Carbopol is added by stirring. After addition of 139 g of Luvitol EHO, neutralize the nozzle with a solution prepared from 83 g of diisopropylamine, 833 g of ethanol and 833 g of water, and then adjust to a solution consisting of 28 g of diisopropylamine, 555 g of ethanol and 555 g of water, to pH 7 , 5. Fill the gel into the tubes.

Claims (8)

A process for the preparation of one-liter 1,1-dioxide amide 6-chloro-4-hydroxy-2methyl-N- (2-pyridyl) -2H-thieno- (2,3-e) -1,2-thiazine-3- carboxylic acids of formula I CH ₃ —CH — 0 — C — O — fl ³ I o wherein R is (C 1 -C ₆ ) -alkyl, (C ₅ -C ₇ ) -cycloalkyl or benzyl, characterized in that the salt of 1,1-dioxide amide is 6-chloro-4-hydroxy-2-methyl-N - (2-Pyridyl) -2H-thieno (2,3-e) -1,2-thiazine-3-carboxylic acid of formula II in which M ⁺ is an alkali or alkaline earth cation or tetraalkylammonium, is reacted in reaction inert, polar, aprotic and anhydrous solvent such as dimethylformamide, dimethylsulfoxide, acetone or 2-butanone, at temperatures between room temperature and the boiling point of the solvent used, with a compound of formula III X I CH ₃ CH-0-C-0-fl II III in which R has the above meaning and X represents halogen. A process according to claim 1, characterized in that in the reaction solution a salt of chlorothenoxycam is prepared in situ by the addition of at least one equivalent of a strong base, preferably in a 3- to 4-fold excess of the strong base. Process according to one of Claims 1 or 2, characterized in that the strong base is alkali carbonate. Process according to one of Claims 1 to 3, characterized in that the strong base is potassium carbonate. Process according to one of Claims 1 to 4, characterized in that the reaction inert polar solvent is acetone. A process according to any one of claims 1 to 5, characterized in that the chlorothenoxicam salt is reacted with a compound of formula II at the reflux temperature of the solvent. Process according to one of Claims 1 to 6, characterized in that sodium iodide is used to accelerate the reaction in up to 3 times excess with respect to the alkylating agent. Process according to one of Claims 1 to 7, characterized in that 1.5 to 2.0 moles of sodium iodide are used per mole of alkylating agent.