NO850725L - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE OXICAM DERIVATIVES. - Google Patents

Description

The present invention relates to the preparation of certain ester derivatives of oxicam (1,1-dioxides of N-hetero-aryl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamides and N-heteroaryl-4-hydroxy -2-methyl-2H-thieno[2,3-e]-1,2-thiazincarboxamides) which are useful oral prodrugs for these nonsteroidal anti-inflammatory oxicams.

The oxicams and their utility as anti-inflammatory and analgesic agents are disclosed in US Patent Nos. 3,591,584,

3,787,324, 3,822,258, 4,180,662 and 4,376,768. US Patent No. 4,309,427 discloses certain ester derivatives of piroxicam, N-(2-pyridyl)-4-hydroxy-2-methyl-2H-1, 2-Benzothiazine-3-carboxamide-1,1-dioxide and its N-(6-methyl-2-pyridyl)-analogues which are useful anti-inflammatory agents, particularly for topical administration. J. Med. Chem. 16, 44-48 (1973) mentions that N-phenyl-4-acetoxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide has moderate anti-inflammatory activity while the corresponding 4-hydroxy -connection has marked activity. The present invention provides a process for the preparation of anti-inflammatory ester drug precursors with formula

or

wherein R is (C2-C8)alkanoyl, benzoyl, toluoyl, (C2-C8)alkylsulfonyl or benzenesulfonyl,

R 2 is 5-methylisoxazol-3-yl or 6-chloro-2-pyridyl, and R 3 is benzoyl, toluoyl, (C 1 -C 8 )alkylsulfonyl or benzene-

sulfony1.

Particularly preferred compounds of formula (I) are those in which is (C 2 -C 8 )alkanoyl, benzoyl or benzenesulfonyl and particularly preferred individual compounds of formula (I) are: N-(5-methylisoxazol-3-yl)-2-methyl- 4-benzoyloxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide;

N-(5-methylisoxazol-3-yl)-2-methyl-4-(n-hexanoyloxy)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide;

N-(6-chloro-2-pyridyl)-2-methyl-4-benzoyloxy-2H-1,2-benzo-thiazine-3-carboxamide 1,1-dioxide;

N-(6-chloro-2-pyridyl)-2-methyl-4-(n-hexanoyloxy)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide; and

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 R 1 is benzoyl or benzenesulfonyl.

Unlike the oxicams from which they are derived, the compounds prepared according to the invention are not enolic acids and they show reduced gastric irritation when compared to the non-esterified oxicams from which they are derived.

The term "drug precursor" refers to compounds which are precursors to drugs and which, after administration and absorption, release the drug in vivo via some metabolic reaction such as hydrolysis.

Pharmaceutical preparations suitable for administration to warm-blooded animals, including humans, comprise a pharmaceutically acceptable carrier and an anti-inflammatory effective amount of a compound of formula (I) or (II). An inflammatory condition in a warm-blooded animal can be treated by administering an anti-inflammatory effective amount of a compound of formula (I) or (II).

While all of the usual routes of administration are usable, the preferred route of administration is the oral route. After absorption in the gastrointestinal tract, the present invention is hydrolyzed in vivo to the corresponding oxicams of formula (I) or (II) where R-^ or R^ is hydrogen, or a salt thereof. As the drug precursors produced according to the invention are not enolic acids, the effect of the acidic oxicam compounds on the gastrointestinal tract is minimized. Furthermore, as gastrointestinal complications have been observed as a serious adverse effect of acidic non-steroidal anti-inflammatory drugs [see e.g. DelFavero in "Side Effeets of Drugs Annual7", Dukes and Elis, Eds. ExcerptaMedica, Amsterdam, 1983, pp. 104-105], the compounds (I) and (II) prepared according to the invention have a decided advantage over the enolic oxicams they are derived from.

In the process for preparing the new oxicamesters, the starting oxicams of formula (II) or (IV) are treated with at least one equimolar amount of a carboxylic acid halide or sulfonyl halide of formula R-X or R-X as outlined below:

where R 1 , R 2 and R 2 are as previously defined, X is chlorine, bromine or iodine and B is a suitable standard base. The reaction usually takes place in a reaction-inert organic solvent under substantially anhydrous conditions in the presence of an equivalent amount of a suitable standard base. Generally, the reaction takes place at a temperature of from about 0°C up to about 50°C for a period of from about half to about 72 hours, although it is usually more convenient to allow the reaction to take place at or around room temperature after mixing the reactants at reduced temperature, e.g. 0 to 10°C.

Although any inert organic solvent may be used, it is generally most desirable to use a solvent such as an aromatic hydrocarbon, e.g. benzene, toluene or xylene, a halogenated lower hydrocarbon, e.g. methylene chloride, chloroform, ethylene dichloride or s-tetrachloroethane, a lower alkyl ketone, e.g. acetone, methyl ethyl ketone or methyl isobutyl ketone, a lower alkyl ester, e.g. methyl acetate, ethyl acetate, isopropyl acetate or methyl proprionate, a lower dialkyl ether, e.g. diethyl ether, diisopropyl ether or di-n-butyl ether, or mixtures thereof.

Suitable standard basic reagents for use in this reaction include alkali metal and alkaline earth metal oxides, bicarbonates and carbonates, as well as tertiary amines such as triethylamine, N-methylpyrrolidine, N-methylmorpholine and pyridine. It should be noted that the standard base used must be present in sufficient quantity to neutralize the liberated hydrogen halide formed by the reaction. Triethylamine is the most preferred standard base because it can be easily removed from the reaction mixture in the form of an insoluble hydrogen halide precipitate.

Alternatively, the compounds of formula (III) and (IV) can be acylated with carboxylic acid anhydrides instead of the above compounds R 1 X and R 3 X as defined above, but where R 1 and R 3 are different from the aforementioned alkylsulfonyl or benzenesulfonyl.

For example, the compound (III) and alkylcarboxylic acid anhydride (R-^^O) are reacted in the presence of one of the reaction-initiated organic solvents above with a molar excess of sodium bicarbonate at room temperature, giving the corresponding product of formula (I) .

The reactions are suitably followed by thin-layer chromatography, thereby determining reaction times sufficient to give a complete reaction and at the same time avoiding unnecessary heating expenses and excess reaction time which can increase the level of by-products and reduce the yield.

The oxicams (III) and (IV) required as starting materials are available by methods well known in the art, see for example the references to oxicams referred to above. The reagents R-^X, R^X and the corresponding acid anhydrides listed above are commercially available or prepared by well-known methods.

The oxicam prodrugs of formula (I) and (II) are evaluated for their anti-inflammatory and analgesic activity according to known methods such as the rat foot edema test

(rat foot edema test), adjuvant-induced arthritis test in rats (rat adjuvant-induced arthritis test) or phenylbenzoquinone-induced writhing test in mice (phenylbenzoquinone-induced writhing test in mice), which have been used previously in the assessment of origin -oxicams and are described in the references referred to above and elsewhere in the literature, see e.g. ABOUT. Winter in "Progress in Drug Research", edited by E. Jucker, Birkhauser Verlag, Basel, vol. 10, 1966, pp. 139-192.

In comparison with the parent oxicams of formula (III)

and (IV), the new prodrugs of formula (I) and (II) have been found to have markedly lower ability to prevent prostaglandin synthesis from arachidonic acid in experiments carried out by a variant of the experimental method of T. J. Carty et al, Prostaglandins 19 , 51-59 (1980). In the modified method, cultures of basophilic leukemia cells (RBL-1) from rats are used, prepared according to the method of Jakschik et al., ibid. 16, 733 (1978) instead of fibroblasts from mice (MC5-5) and synovial cell cultures from rabbits. Thus, the new compounds in themselves are relatively inactive as anti-inflammatory agents, but they give rise to an active anti-inflammatory compound upon hydrolysis in vivo. As the compounds (I) and (II) are not enolic acids and it is known that the hydrolysis takes place after the drug precursor leaves the stomach, they will significantly reduce the irritation of the stomach caused by oral administration of the enolic oxicams from which they are derived.

On a molar basis, the present oxicam prodrugs are dosed at the same level and frequency as the known oxicams from which they are derived. However, the non-enolic nature of the present compounds will generally permit higher tolerated oral doses, when such doses are necessary to control pain and inflammation.

The present oxicam prodrugs are also made in the same manner and administered via the same route as the known oxicams, as described in the above-cited references. The preferred route of administration is the oral; thus, particular advantage is taken of the non-enolic character of the present compounds.

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

EXAMPLE 1

N-(5-methylisoxazol-3-yl)-2-methyl-4-benzoyloxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide

2.0 g (6.0 mmol) N-(5-methylisoxazol-3-yl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (isoxy-com ) is mixed with 35 ml of methylene chloride under a nitrogen atmosphere. To the resulting slurry is added 0.92 ml (6.6 mmol) of triethylamine, the mixture is stirred to dissolve and then cooled in an ice-water bath. A solution of benzoyl chloride, 0.77 mL, (6.6 mmol) in 5 mL of methylene chloride was added dropwise over 5 minutes and the mixture was stirred at room temperature overnight. After extraction once with 50 mL water, twice with 50 mL portions of saturated sodium bicarbonate solution, and once with 50 mL brine solution, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated in vacuo to gave a foam. The foam was triturated with isopropyl ether, filtered to give 2.15 g of gray solid, m.p. 203-205°C (dec). This was dissolved in 75 ml of hot acetonitrile, filtered, cooled to room temperature and allowed to stand overnight to give 1.50 g (57.7%) of beige crystals, m.p. 210-212°C (dec).

Analysis:

Calculated for C 2 H 2 O 2 S: C, 57.40; H, 3.90; N, 9.56. Found: C, 57.10; H, 3.96; N, 9.63. Infrared spectrum (KBr) micron: 5.7 (ester carbonyl),

5.93 (amide carbonyl), 7.45, 8.55.

EXAMPLE 2

N-(5-methylisoxazol-5-yl)-2-methyl-4-(n-hexanoyloxy)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide

The procedure of Example 1 was repeated, but with n-hexanoyl chloride instead of benzoyl chloride, and gave 2.54 of crude product which was triturated with 70 ml of isopropyl ether at room temperature, filtered to give 1.84 g of solid, m.p. 142-146°C. After recrystallization from ethanol, 1.08 g (41.5%) of colorless crystals appeared, m.p. 175-177°C (dec).

Analysis:

Calculated for C 2 0 H 2 ^Og1S^S: C, 55.42; H, 5.35; N, 9.69. Found: C, 55.32; H, 5.52; N, 9.65. Infrared spectrum (KBr) micron: 5.63 (ester carbonyl),

5.92 (amide carbonyl), 7.45, 8.45.

EXAMPLE 3

N-(5-methylisoxazol-3-yl)-2-methyl-4-(2,2-dimethyl-pentanoyloxy)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

Reaction of 972 mg (2.90 mmol) N-(5-methylisoxazol-3-yl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine 1,1-dioxide in 10 ml methylene chloride, 0.4 5 ml (3.20 mmol) of triethylamine, 4 76 mg (3.20 mmol) of 2,2-dimethylpentanoic acid chloride in 5 ml of methylene chloride by the procedure in Example 1, extraction of the reaction mixture twice with 25 ml portions of water, twice with 25 ml of saturated sodium bicarbonate solution, once with brine, drying over anhydrous sodium sulfate and evaporation of the solvent gave a beige colored semi-solid. This was triturated with ethyl ether (15 mL), slurried overnight, and the resulting mixture was filtered to give 1.05 g of an off-white solid. The solid was taken up in hot ethyl acetate (20 mL), filtered to remove insoluble material, and the filtrate was cooled to room temperature. Filtration and air drying yielded 448.5 mg of colorless crystals, m.p. 213-215°C (34.5% yield).

Analysis:

Calculated for c2i<H2>5°6<N>3<S:>C'56'36;H'5/63'* N'9/39. Found: C, 56.18; H, 5.63; N, 9.41.

Infrared spectrum (KBr) micron: 5.67, 5.88, 6.14,

7.47, 8.48. Mass spectrum m/e: 447 (molecular ions).

EXAMPLE 4

N-(5-methylisoxazol-3-yl)-2-methyl-4-benzenesulfonyloxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide

The procedure in Example 1 was repeated on a 3.0 mmol scale with benzenesulfonyl chloride instead of benzoyl chloride. After addition of the benzenesulfonyl chloride, a precipitate was formed after stirring for 45 minutes at room temperature. After 60 minutes the mixture was filtered, washed with a small amount of methylene chloride to give 0.76 g of colorless solid, m.p. 218-220°C (dec). This was taken up in 15 ml of hot acetonitrile, filtered and the filtrate was cooled to room temperature and allowed to stand overnight. On filtration and drying, 0.51 g (37%) of colorless crystals appeared, m.p. 225-226°C (dec).

Analysis:

Calculated for C2oHl7°7N3<S>2<:><C>' 50'52;H'3'60'" N'8.84. Found: C, 50.60; H, 3.73; N, 8 .83.Infrared spectrum (KBr) micron: 2.98, 5.95, 7.44-7.55,

8.35-8.60.

EXAMPLE 5

N-(6-chloro-2-pyridyl)-2-methyl-4-benzoyloxy-2H-1,2-benzothiazine-3-carboxamide

1,1-dioxide

Under a nitrogen atmosphere, 987 mg (2.70 mmol) of N-(6-chloro-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide and 15 ml methylene chloride united. To the resulting suspension was added 0.41 mL (2.97 mmol) of triethylamine, the resulting pale green solution was cooled in an ice/water bath, and 0.35 mL (2.97 mmol) of benzoyl chloride in 5 mL of methylene chloride was added dropwise over three minutes.

The resulting mixture was stirred at room temperature overnight, extracted with water (2 x 25 mL), saturated sodium bicarbonate solution (2 x 25 mL), brine (1 x 25 mL) and dried (Na 2 SO 4 ). Evaporation of the solvent from the filtrate gave a colorless solid which was triturated with isopropyl ether and stirred overnight at room temperature. Filtration and drying of the precipitated product gave 1.1 g of colorless solid, m.p. 192-195°C (dec). Recrystallization from hot acetonitrile gave 0.72 g (56.7%) crystals, m.p. 195-196°C (dec).

Analysis:

Calculated for C^H^O^CIS: C, 56.23; H, 3.43; N, 8.94. Found: C, 56.02; H, 3.48; N, 8.93. Infrared spectrum (KBr) micron: 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 1,1 dioxide

The procedure of Example 5 was repeated on a 1.35 millimolar scale in 9 ml of methylene chloride and using 0.21 ml (1.49 mmol) of n-hexanoyl chloride as acylating agent in 1 ml of the same solvent. After addition of the acid chloride over two minutes, the resulting clear yellow solution was stirred at ambient temperature for 4 hours and then washed and dried in the usual manner. Evaporation of the solvent gave a yellow gum which crystallized on standing. This was taken up in 50 ml of isopropanol, filtered and allowed to stand at room temperature overnight to give 0.31 g (4 9.5%) of colorless crystals, m.p. 154-156°C (dec).

Analysis:

Calculated for C^H^O^CIS: C, 54 .37 ; H, 4.78; N, 9.06. Found: C, 54.13; H, 4.91; N, 8.91. Infrared spectrum (KBr) micron: 5.65, 5.95, 7.47, 8.5.

EXAMPLE 7

N-(6-chloro-2-pyridyl)-2-methyl-4-(2,2-dimethyl-pentanoyloxy)-2H-1,2-benzothiazine-3-carboxamide

1,1-dioxide

The procedure in Example 3 was repeated, but using 1.1 g (3.0 mmol) of N-(6-chloro-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3 -carboxamide 1,1-dioxide as starting material-

le, and it gave 1.2 g (84%) of impure product, m.p. 171-17.3°C.

Crystallization from hot ethyl acetate gave 0.70 g (49%) of a colorless solid, m.p. 171-173°C.

Analysis:

Calculated for <C>22<H>2405N3SC1: C, 55.29; H, 5.06; N, 8.79. Found: C, 55.19; H, 5.08; N, 8.76. Infrared spectrum (KBr) micron: 3.04, 3.38, 5.66, 5.94, 7.35, 8.55 Mass spectrum m/e: 477 (origin) 365, 301, 283, 237, 173, 145 ,

128, 104, 85 (base stop).

EXAMPLE 8

N-(6-chloro-2-pyridyl)-2-methyl-4-benzenesulfonyloxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide

The procedure of Example 5 was repeated on a 1.26 millimolar scale in 9 ml of methylene chloride and with acylation with benzenesulfonyl chloride solution. After stirring at room temperature for 4.5 hours, the crude product was isolated as before to give 0.71 g of solid. This was taken up in 50 ml of hot isopropanol, filtered, cooled and the product was collected by filtration and drying in vacuo, 0.33 g (51.8%), m.p. 190-191°C.

Analysis:

Calcd for C 21 H 16 O 6 N 3 S 2 C 1 : C, 49.85; H, 3.19; N, 8.30. Found: C, 49.75; H, 3.32; N, 8.24. Infrared spectrum (KBr) micron: 5.95, 7.4, 8.5.

Claims (9)

1. Procedure for the preparation of a compound of formula: wherein is (C 2 -C 8 )alkanoyl, benzoyl, toluoyl, (C 1 -C 8 )alkylsulfonyl or benzenesulfonyl; R 1 is 5-methylisoxazol-3-yl or 6-chloro-2-pyridy 1; and R 1 is benzoyl, toluoyl, (C 1 -C 8 )alkylsulfonyl or benzenesulfonyl, characterized in that a compound of formula is reacted with an equimolar amount of a carboxylic acid halide or sulfonyl halide of formula RX where R is R^ or R^ , in the presence of a reaction-inert organic solvent where R1' R2 °^ R3 is SOm previously defined and X is chlorine, bromine or iodine. 2. Method according to claim 1, characterized in that said reaction takes place at a temperature from 0 to 50°C. 3. Process according to claim 1 or 2 when it takes place in the presence of a standard base selected from an alkali metal or alkaline earth metal oxide, bicarbonate or carbonate, or a tertiary amine selected from triethylamine, N-methylpyrrolidene, N-methylmorpholine or pyridine. 4. A process according to any one of claims 1 to 3 for the preparation of a compound of formula characterized in that a compound of formula (III) as defined in claim 1 is reacted with a carboxylic acid halide or sulfonyl halide of formula R^X. 5. Method according to any of claims 1 to 3 for the preparation of a compound of formula characterized in that a compound of formula (IV) as defined in claim 1 is reacted with a carboxylic acid halide or sulfonyl halide of formula R-^X. 6. Method according to claim 4, where R 1 is (C 2 ~ C 8 )alkanoyl, benzoyl or benzenesulfonyl. 7. Method according to claim 6, characterized in that said compound which is produced is N-(5-methylisoxazol-3-yl)-2-methyl-4-benzoyloxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, N-(5-methylisoxazol-3-yl)-2-methyl-4-(n-hexanoyl-oxy)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, N-(6-chloro-2-pyridyl)-2-methyl-4-benzoyloxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, N-(6-chloro-2-pyridyl)-2-methyl-4-(n-hexanoyl-oxy)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, or N-(6-chloro-2-pyridyl)-2-methyl-4-benzenesulfonyl-oxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide. 8. Method according to claim 5 where R 1 is benzoyl or benzenesulphonyl. 9. Method according to claim 8, characterized in that said compound which is produced is: N-(2-pyridyl)-2-methyl-4-benzoyloxy-2H-thieno-[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide, or N-(2-pyridyl)-2-methyl-4-benzenesulfonyloxy-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide.