LU85780A1 - NOVEL ENOLIC ESTERS PRECURSOR OF DRUGS AND PHARMACEUTICAL COMPOSITION CONTAINING THEM - Google Patents

Description

The present invention relates to certain esters of oxicams (1,-dioxides of N-hetero-aryl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamides and N-hetero-aryl-4 -hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-5 carboxamides) which are useful oral prodrugs of these non-stereoidic anti-inflammatory oxicams.

Oxicams and their utility as anti-inflammatory and analgesic agents are disclosed in United States Patent Nos. 3,591,584, No. 3,787,324; No. 3,822,258; No. 4,180,662 and No. 4,376,768. United States Patent No. 4,309,427 discloses certain esters of piroxicam, N- (2-pyridyl) -4-hydroxy 1,1-dioxide -2-methyl ~ 2H-1,2-benzothiazine-3-carboxamide "and its analogue N- (6-methyl-2-pyridic), which are useful anti-inflammatory agents, in particular for topical administration. The review 3_. Med. Chem., 16, 44-48 (1 973) discloses the moderate anti-inflammatory activity of N-phenyl-4-acetoxy-1,1-dioxide-2-methyl-2H-1,2-benzothiazine-3-carboxamide, whereas the corresponding 4-hydroxylic compound has a pronounced activity.

The present invention provides anti-inflammatory pro-drugs which are esters of the formula

- AT

2 OR, / v ^ V / conhr2 5 II (I) r \

O O

Λ 10 J * 3 OR [l I f (II) '-ks ^ CH3 / \

0 O

Wherein R 1 is a C 2 -C 6 alkanoyl, benzoyl toluoyl, (C 1 -C 8 alkyl) sulfonyl or benzenesul-, fonyl; R2 is a 5-methylisoxazole-3-yl or 6-20 chloro-2-pyridyl group; and

Rg is a benzoyl, toluoyl, (C1-C6 alkyl) sulfonyl or benzenesulfonyl group.

Particularly preferred compounds of formula (I) are those in which R 1 is a C 2 -C 6 alkanoyl, benzoyl or benzenesulfonyl and particularly preferred individual compounds of formula (I) are the compounds: 1.1- N- dioxide ( 5-methylisoxazole-3-yl) -2-methyl-4-benzoyloxy-2H-1,2-benzothiazine-3-carboxamide; N- (5-methylisoxazole-3-yl) -2-methyl-4- (n-hexanoyloxy) -2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide; 1.1- N- (6-chloro-2-pyridyl) -2-methyl-4-benzoyloxy-2H-1,2-benzothiazine-3-carboxamide dioxide; 1.1- N- (6-chloro-2-pyridyl) -2-methyl-35 4- (n-hexanoyloxy) -2H-1,2-benzothiazine-3-carboxamide dioxide; and 3 N-(6-chloro-2-pyridyl) -2-methyl-4-benzenesulfonyloxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide.

Particularly preferred compounds of formula (II) are those in which is a benzoyl or benzenesulfonyl group.

Unlike the corresponding oxicams, the compounds of the invention are not enolic acids and they show reduced gastric irritation compared to the corresponding unesterified oxicam.

The term "prodrug" refers to compounds which are drug precursors and which * after administration and absorption, release the drug in vivo by a certain metabolic process such as a hydrolysis process.

The present invention also relates to pharmaceutical compositions which are suitable for administration to warm-blooded animals, including humans, which composition comprises a pharmaceutically acceptable carrier and an anti-inflammatory effective amount of a compound of formula (I) or (II), this composition being intended for the treatment of an inflammatory condition in a warm-blooded animal requiring such treatment by the administration of an anti-inflammatory amount of a compound of formula (I) or (II).

Although all of the usual routes of administration are useful with the compounds of the invention, the preferred route of administration is the oral route. After gastrointestinal absorption, the compounds of the invention are hydrolyzed in vivo to the corresponding oxicams of formula (I) or (II) in which or R 1 represents hydrogen, or a salt of these compounds. Since the pro-drugs of the invention are not enolic acids, exposure of the gastrointestinal tract to acid oxicams is therefore minimized. In addition, 35 whereas gastrointestinal complications have been observed as the main adverse reaction of acidic non-stereoidal anti-inflammatory drugs [see, for example, DelFavero> in "Side Effects of Drugs Annual 7", Dukes and Elis, Eds ., Excerpta Medica, Amsterdam, 5 1983, pages 104-105], the compounds (I) and (II) of the invention offer a distinct advantage over the corresponding enolic oxicams.

In the process for the preparation of the new oxicam esters of the invention, the corresponding oxicam of formula (III) or (IV) is treated, for example, with * at least an equimolar amount of a halide of carboxylic acid or sulfonyl halide of formula RX or 3 RX as indicated below:

OH

1 5 CONHR2

I I + Rxx -S — ► (I) + EX

^ A.S-NCH3 B

O O

(III) 20 F jf)

CCNH ^ TK

l! _1 JcH, + r3x-B * (II) + Bx / \ 25 0 0 (IV) 12 3 where R, R and R have the definitions given above,: X is a chloro, bromo or iodo radical and B is a suitable normal base. The process is normally carried out in an organic solvent inert to the reaction under substantially anhydrous conditions in the presence of an equivalent amount of a suitable normal base. In general, the reaction is carried out at a temperature of about 0 to about 50 ° C for a period of about 0.5 to about 72 hours, although it is usually very advantageous to conduct the reaction room temperature or around room temperature after the reactants have been brought together at reduced temperature, for example from 0 to 10 ° C.

Although any inert organic solvent can be used, it is generally very advantageous to use a solvent such as an aromatic hydrocarbon, for example, benzene, toluene or xylene; a halogenated lower hydrocarbon, for example, methylene chloride, chloro-, form, dichlorethylene or s-tetrachlorethane; a lower alkyl ketone, for example, acetone, methyl ethyl ketone or methyl isobutyl ketone; a lower alkyl ester, for example methyl acetate, ethyl acetate, isopropyl acetate or methyl propionate; a lower dialkyl ether, for example, diethyl ether, diisopropyl ether or di-n-butyl ether; or a mixture of these solvents. Advantageous conventional bases to be used in this process include the oxides, bicarbonates and carbonates of alkali metals and alkaline earth metals as well as tertiary amines such as triethylamine, N-methylpyrroli-dine, N-methylmorpholine and pyridine. It should be noted that the conventional base used must be present in an amount sufficient to neutralize the released hydrogen halide which is formed in the reaction.

Triethylamine is the most suitable conventional base because it can be readily removed from the reaction mixture as an insoluble halogen hydrate precipitate.

Alternatively, the compounds of formulas (III) and (IV) may be acylated with anhydrides 1 3 of carboxylic acids in place of the compounds RX and RX above as defined in the above, but in which R and R represent something other than the said alkylsulfonyl or benzenesulfonyl group. For example, the compound (III) and an alkylcarboxylic acid anhydride 1 (R) 20 are reacted in the presence of one of the abovementioned organic solvents inert towards the reaction with a molar excess of bicarbonate of sodium at room temperature to form the corresponding product of formula (I).

The reactions are advantageously monitored. by thin layer chromatography, thereby determining sufficient reaction times to allow! be a complete reaction while avoiding unnecessary heating costs and excessive reaction time, which can increase the rate of by-products and reduce yields.

The oxicams (III) and (IV) necessary as starting compounds can be obtained by methods well known in the prior art, for which reference is made, for example, to the aforementioned references concerning oxi-3 cams. The reagents R X, R X and the corresponding acid anhydrides indicated above are either commercially available or are prepared by well known methods.

The oxicam precursor drugs of formulas (I) and (II) are subjected to an evaluation of anti-inflammatory and analgesic activity in accordance with known methods such as the test for rat paw edema, the test for adjuvant-induced arthritis in rats or the phenyl-benzoquinone-induced muscle tension test in mice, as previously used for the evaluation of corresponding oxicams and as described in the above references and in d 'other publications; see, for example, C. A. Winter, in "Progress in Drug Research", published by E. Jucker, Birkhauser Verlag, Basel, volume 10, 1966, pages 139-192.

7s

Compared to the corresponding oxicams of formulas (III) and (IV), it can be seen that the new prodrugs of formulas (I) and (II) have a markedly reduced ability to inhibit the synthesis of prostaglandins 5 from arachidonic acid. in tests carried out according to a variant of the method of TJ Carty et al., Prostaglandins, 19, 51-59 (1980). In the modified version of this method, cultures of rat basophilic leukemia cells (RBL-1) prepared by method 10 of Jakschik et al., Ibid. , 16, 733 (1978) are = · used in place of cultures of mouse fibroblasts (MG5-5) and rabbit synovial cells. Thus, the compounds of the invention are themselves relatively inactive as anti-inflammatory agents, but they generate an active anti-inflammatory compound upon hydrolysis in vivo. Since compounds (I) and (II) are not enolic acids and it is known that hydrolysis takes place after the prodrug has left the stomach, they significantly reduce the gastric irritation due to oral administration of the corresponding enolic oxicams.

On a molar basis, the oxicam precursor drugs of the invention are generally administered at the same dose and at the same frequency as the known oxicams from which they can be obtained. However, the non-enolic nature of the compounds of the invention generally allows higher tolerated oral doses when the administration of these higher doses is necessary to combat pain and inflammation.

The oxicam precursor drugs of the invention are also formulated in the same manner and administered by the same routes as known oxicams, as described in the aforementioned references. The preferred route of administration is the oral route, thus taking particular advantage of the non-enolic nature of the compounds of the invention.

8

The present invention is illustrated by the following examples, but is not limited to the particular details given in these examples.

EXAMPLE 1 5 1,1-N-dioxide (5-methylisoxazole-3 ~ yl) -2-methyl-4-benzoyloxy-2H ~ 1,2-benzothiazine-3-carboxamide (I, Rj "CgHjCO, R2- = ^ {10

Operating under a nitrogen atmosphere, 2.0 g (6.0 mmol) of N- (5-methyl-isoxazole-3-yl) -2-methyl-4-hydroxy- 1,1-dioxide are mixed. 2H-1,2-benzothiazine-15 3-carboxamide (isoxicam) with 35 ml of methylene chloride. 0.92 ml (6.6 mmol) of triethylamine is added to the resulting suspension, the mixture is stirred to effect dissolution, then cooled in an ice-water bath. A solution of benzoyl chloride, 0.77 ml (6.6 mmol), in 5 ml of methylene chloride is added dropwise over 5 minutes and the mixture is stirred at room temperature for approximately 18 h. After extraction once with 50 ml of water, twice with 50 ml portions of saturated sodium bicarbonate solution and once with 50 ml of salt solution, the organic phase is dried over anhydrous sodium sulfate, we . the filter and the filtrate is evaporated under vacuum to obtain a foam. The foam is triturated with isopropyl ether and obtained by filtering 2.15 g of a gray solid substance, melting point 203-205 ° C (decomposition).

This substance is dissolved in 75 ml of hot acetonitrile, the solution is filtered, allowed to cool to room temperature and allowed to stand for approximately 18 h to obtain 1.50 g (57.7%) of beige crystals having 35 a melting point of 210-212 ° C (decomposition).

9

Analysis, calculated for ^ 21 ^ 17 ^ 6 ^ 3 ^: G, 57.40; H, 3.90; N, 9.56. found: C, 57.10; H, 3.96; N, 9.63.

’Infrared spectrum (KBr), micrometers: 5.75 (ester carbonyl), 5.93 (amide carbonyl), 7.45, 8.55.

EXAMPLE 2 1.1- N- (5-methylisoxazole-3-yl) -2-methyl-4- (n-hexanoyloxy) -2H-1,2-benzothiazine-3-carboxamide 10 dioxide (I 'R1' * 2 1 -dd,% Λοη3

The procedure of Example 15 1 was repeated, but using n-hexanoyl chloride in place of benzoyl chloride to obtain 2.54 g of crude product which was triturated with 70 ml of isopropyl ether to at room temperature, and filtered to give 1.84 g of a solid material, melting at 142-146 ° C. After recrystallization from ethanol, 1.08 g (41.5%) of colorless crystals were obtained, melting at 175-177 ° C (decomposition).

Analysis, calculated for ^ 20 ^ 23 ^^ 4 ^: G, 55.42; H, 5.35; N, 9.69. found: G, 55.32; H, 5.52; N, 9.65.

Infrared spectrum (KBr), micrometers: 5.63 (ester carbonyl), 5.92 (amide carbonyl), 7.45, 8.45.

EXAMPLE 3 1.1- N- (5-methylisoxazole-3-yl) -2-methyl-4- (2,2-dimethylpentanoyloxy) -2H-1,2-benzothiazine-3-carboxamide dioxide {I, Rx = CH3CH2CH2C (CH3) 2CO, R2 * ~ r-η 35 By reacting 972 mg (2.90 mmol) of 1.1- N-dioxide (5-methylisoxazole-3-yl) -2-methyl-4- 10 "hydroxy- 2H-1,2-benzothiazine in 10 ml of methylene chloride, 0.45 ml (3.20 mmol) of triethylamine, 476 mg (3.20 mmol) of 2,2-dimethylpen-, tanoic acid chloride in 5 ml of methylene chloride by the procedure of Example 1, extracting the reaction mixture twice with 25 ml portions of water, twice with saturated sodium bicarbonate solution, once with a solution salt, by drying over anhydrous sodium sulfate and evaporating the solvent, a semi-solid substance beige in color was obtained. This material was triturated with ethyl ether (15 ml), kept in suspension for about 18 hours and the resulting mixture was filtered to give 1.05 g of a slightly dirty white solid. The solid was taken up in hot ethyl acetate (20 ml), filtered to remove insoluble matter and the filtrate was cooled to room temperature. By filtration and air drying, 448.5 mg of colorless crystals were obtained, melting at 213-215 ° C (yield 34.5¾).

Analysis, calculated for C0 „H„ -0-N-S: 2i 25 O i C, 56.36; H, 5.63; N, 9.39. found: C, 56.18; H, 5.63; N, 9.41.

Infrared spectrum (KBr), micrometers: 5.67, 5.88, 6.14, 7.47, 8.48.

25 Mass spectrum, m / e: 447 (molecular ion).

EXAMPLE 4 N- (5-methylisoxazole-3-yl) -2-methyl-4-benzenesulfonyloxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (I "! - C6H3SO2, R2 - rf | (iV0> -ch3

The procedure of Example 35 1 was repeated on a 3.0 millimolar scale using 11 * benzenesulfonyl chloride in place of benzoyl chloride. After addition of benzenesulfonyl chloride, a precipitate formed after stirring for 45 minutes at room temperature. After 60 minutes the mixture was filtered and washed with a small amount of methylene chloride to give 0.76 g of a colorless solid melting at 218-220 ° C (decomposition). This material was taken up in 15 ml of hot acetonitrile, filtered, and the filtrate was cooled to room temperature and allowed to stand for about 18 hours. After filtration and drying, 0.51 g (37%) of colorless crystals were obtained, melting at 225-226 ° C (decomposition).

Analysis, calculated for ^ 20 ^ 70. ^ 282 'C, 50.52; H, 3.60; N, 8.84.

15 found: C, 50.60; H, 3.73; N, 8.83.

Infrared spectrum (KBr), micrometers: 2.98, 5.95, 7.44-7.55, 8.35-8.60.

EXAMPLE 5 N- (6-chloro-2-pyridyl) -2-methyl-4-benzoyloxy-20 2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (I, ftj - c6h5co, r2 = 25 ___

By operating under a nitrogen atmosphere, 987 mg (2.70 mmol) of 1,1-dioxide of N- (6-chloro-2-pyridyl) -2-methyl-4-hydroxy-2H-1 were combined, 2-benzothiazine-3-car ~ boxamide with 15 ml of methylene chloride. 0.41 ml (2.97 mmol) of triethylamine was added to the resulting suspension, the resulting pale green solution was cooled in an ice-water bath and added dropwise over 3 minutes 0.35 ml (2.97 mmol) of benzoyl chloride in 5 ml of methylene chloride. The resulting mixture was stirred at room temperature for about 12-18 hours, extracted with water (2 x 25 ml), with saturated sodium bicarbonate solution (2 x 25 ml), salt solution ( 1 x 25 ml), and dried (Na2SO ^). By evaporation of the solvent from the filtrate, a colorless solid was obtained which was triturated with isopropyl ether and stirred for about 18 hours at room temperature. By filtration and drying of the precipitated product, 1.1 g of a colorless solid substance, melting at 192-195 ° C., was obtained. (decomposition). By recrystallization from hot acetonitrile, 0.72 g (56.7%) of crystals was obtained, melting at 195-196 ° C (decomposition).

Analysis, calculated for C22H ^ 605N3C1S: C, 56.23; H, 3.43; N, 8.94. found: C, 56.02; H, 3.48; N, 8.93 15 Infrared spectrum (KBr), micrometers: 2.98, 5.70, 5.95, 7.38, 8.4.

EXAMPLE 6 N- (6-chloro-2-pyridyl) -2-methyl-4- (n-hexanoyloxy) -2H-1,2-benzothiazine-3-carboxamide 20 (I, Rx = n -CH3 (CH2) 4CO, R2 The procedure of Example 5 was repeated on a 1.35 millimolar scale in 9 ml of methylene chloride using 0.21 ml (1.49 mmol) of n-hexanoyl chloride as acylating agent in 1 ml of the same solvent After adding the acid chloride solution in 2 minutes, the resulting light yellow solution was stirred at room temperature for 4 hours, then washed and dried in the usual manner. Evaporation of the solvent gave a yellow gum which crystallized on standing. This gum was taken up in 50 ml of isopropanol, filtered and allowed to stand at room temperature for about 18 hours, giving 0.31 g (49.5%) of colorless crystals, melting at 154-156 ° C (decomposition).

Analysis, calculated for C21H22 ° 5N3C · * · ^: C, 54.37; H, 4.78; N, 9.06.

5 found: C, 54.13; H, 4.91; N, 8.91.

Infrared spectrum (KBr) micrometers: 5.65, 5.95, 7.47, 8.5.

EXAMPLE 7, N- (6-chloro-2-pyridyl) -2-methyl-4- (2,2-10 dimethylpentanoyloxy) -2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide

The procedure of Example 3 was repeated, but using 1.1 g (3.0 mmol) of N- (6-chloro-2-pyridyl) -2-methyl-4- 1,1-dioxide hydroxy-2H-1, 2-benzo-20 thiazine-3-carboxamide as starting material to obtain 1.2 g (84%) of crude product, melting at 171-173 ° C. By crystallization from hot ethyl acetate, 0.70 g (49%) of a colorless solid was obtained, melting at 171-173 ° C.

25 Analysis, calculated for ^ 22 ^ 24 ^ 5 ^ 3 ^^: G, 55.29; H, 5.06; N, 8.79. found: C, 55.19; H, 5.08; N, 8.76.

Infrared spectrum (KBr), micrometers: 3.04, 3.38, 5.66, 5.94, 7.35, 8.55.

30 Mass spectrum, m / e: 477 (mother substance) 365, 301, 283, 237, 173, 145, 128, 104, 85 (base peak).

♦ * EXAMPLE 8 N- (6-chloro-2-pyridyl) -2-methyl-4-benzene-sulfonyloxy-2H-1,2-benzothiazine-3-carboxamide 5 <1. h * C6H5SO2; R2)

The procedure of Example * Ίο 5 was repeated on a 1.26 millimolar scale in 9 ml of methylene chloride and carrying out the acylation with a benzenesulfonyl chloride solution. After stirring at room temperature for 4.5 hours, the crude product was isolated as above to obtain 0.71 g of solid material Ί5. This material was taken up in 50 ml of hot isopropanol, filtered, cooled and the product was collected by filtration and drying under vacuum, 0.33 g (51.8%), melting point 190-191 ° C.

Analysis, calculated for C2.jH.j g0gNgS2Cl: 20 G, 49.85; H, 3.19; N, 8.30 found: C, 49.75; H, 3.32; N, 8.24.

Infrared spectrum (KBr), micrometers: 5.95, 7.4, 8.5.

EXAMPLE 9 N- (2-Pyridyl) -2-methyl-4-benzenesulfonyl-oxy-2H-1,2-thieno [2,3-e] thiazine-3-carboxamide (II, 1,1-dioxide C6H5S02, R2 = pyridyl)

0.092 ml (0.66 mmol) of triethylamine was added under a nitrogen atmosphere to a mixture of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2- 1,1-dioxide thieno [2,3-e] thiazine-3-carboxamide (0.20 g, 0.6 mmol) and 20 ml of methylene chloride. 0.115 ml (0.9 mmol) of benzenesulfonyl chloride was added to the resulting solution and the mixture was stirred at room temperature for about 18 hours. The mixture was washed with sodium bicarbonate solution, salt solution, dried (Na2SO4) and the solvent was evaporated to give a yellow oil. This oil was stirred with ethyl ether under nitrogen and the precipitated product was collected by filtration and dried in vacuo to give 0.192 g (66.9%) solid, melting point 175-176 ° C.

. Analysis, calculated for gH1506N3S3.0.25H20: 10 C, 47.94; H, 3.28; N, 8.83 * found C, 47.70; H, 3.14; N, 9.14.

Infrared spectrum (KBr), micrometers: 5.91, 7.23, 7.5, 8.3, 8.4, 8.51, 8.61.

Claims (8)

1. Compound, characterized in that it corresponds to the formula OR · ORg l \\ 2. Compound according to claim 1, characterized in that it corresponds to the formula OR, ^ \ A ^ com2 20. l 1 <^ AsS ^! Ch, Λ 3 0 0 3. Compound according to claim 1, character-ized in that it corresponds to the formula OR 3 __ Li L · / \ 30 0 0 4. Compound according to claim 2, characterized in that R ^ is a C8 to C8 alkanoyl group, benzoyl or benzenesulfonyl. 9, 17 / 5. N- (5-methylisoxazole-3-yl) -2-metliyl-4-benzoyloxy-2H-1,2H-1,2-benzothiazine-3-carboxamide, 1,1-N-dioxide ( 5-methylisoxazole-3-yl) -2-methyl-4- (n-hexanoyloxy) —2H — 1,2-benzothiazine-3-carboxa-5 mide, N-1,1-dioxide (6-chloro- 2-pyridyl) -2-methyl-4-benzoyloxy-2H-1,2-benzothiazine-3-carboxamide, N-1,1-dioxide (6-chloro-2-pyridyl) -2-s methyl-4 - (n-hexanoyloxy) ~ 2H-1, 2-benzothiazine-3-carboxamide 10, or N-1,1-dioxide (6-chloro-2-pyridyl) -2-methyl-4-benzenesulfonyloxy- 2H-1,2-Benzothiazine-3-carboxamide according to claim 4. 5 CONHR2 / S CONH-U ^ t J ζΧΛ or / \ / \ 0 0 0 0 5 10 * in which R ^ is a C 2 -C 6 alkanoyl group, ben zoyl, toluoyl, (C 1 -C alkyl) sulfonyl or benzene -sulfonyl; R2 is a 5-methylisoxazole-3-yl or 6-chloro-2-pyridyl group; and Rg is a benzoyl, toluoyl, (C1-C6 alkyl) sulfonyl or benzenesulfonyl group. 6. Compound according to claim 3, character-ized in that R ^ is a benzoyl or benzenesulfonyl group. 7. N- (2-pyridyl) -2-methyl-4-benzoyloxy-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide j 1,1-dioxide or 1, N- (2-pyridyl) -2-methyl-4-benzenesul-fonyloxy-2H-thieno [2,3-e] -1,2-thiazine ~ 3-carboxamide 1-dioxide according to claim 6. 8. Pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and an anti-inflammatory amount of a compound according to claim 1. *