NL8500485A - LEADERS OF ANTI-INFLAMMATORY OXICAMS. - Google Patents

Description

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Precursors of anti-inflammatory oxicamen ί

The invention relates to certain ester derivatives of axicamsn "(1,1-dioxides of N-hetercaryl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamides and N-heteroary 1-4- hydroxy-2-methyl-2H-thieno {2,3-e} -1,2-thiazine carboxamides) which are useful oral precursors of these nanoteroid anti-inflammatory oxicams.

The oxicams and their usefulness as anti-inflammatory and analgesic agents are described in U.S.-A-3,591,584. 3,787,324? 3,822,258? 4,180,662 and 4,376,768. U.S. 4,309,427 10 describes certain ester derivatives of piroxicam, N- (2-pyridy1) .- 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, and the analogous N- (6-methyl-2-pyridyl) compound which are useful anti-inflammatory agents, especially for topical administration. J. Med. Chem., 16, 44-48 (19731, reports that 15 N-phenyl-4-acetoxy-2-irethyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide has moderate anti-inflammatory activity, while the corresponding 4-hydroxy compound had a pronounced activity.

The invention provides esters which are precursors of anti-inflammatory compounds. These esters are of formula 1 or 2, wherein R 1 is (C 2 -C 6} alkanoyl, benzoyl, toluoyl, (C 1 -C 18 alkylsulfonyl or benzenesulfonyl), R 2 is 5-methylisoxazol-3-yl or 6-chloro-2-pyridy 1? and R 8 is benzoyl, toluoyl, (C 1 -C 18 alkylsulfonyl or benzene-sulfonyl).

Particularly preferred compounds of formula 1 are those wherein R 1 (C 2 -C 6) is alkanoyl, benzoyl or benzenesulfonyl, and especially preferred compounds of formula 1 are: 3Q N- (5-methylisoxazole-3-) yl) -2-methyl-4-benzoyloxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide? N- (5-methylisoxazol-3-yl I-2-methyl-4- (n-hexanoyl- ....

BAqSF§'e'W 8 5 -2- αχγ} -2Η-1,2-ben2Qthiazine ~ 3-carfaoxand.de · - !, 1-dioxide; Ν- (6-chloro-2-pyridyl) -2-methyl-4-benzoyloxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide; Ν- (6-c-corcor-2-pfyridyl) -2-irethyl-4- (n-benzoyloxy) -5 2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide; and N- (6-chloro-2-pyridi-11-2-ethyl-4-benzenesulfanyl-oxy-2H-1,2-benzothiazine-3-caiphoxideside 1,1-dioxide.

Particularly preferred compounds of formula 2 are those wherein benzoyl or benzenesulfon-10 is phenyl.

In contrast to the axycams from which they derive, the compounds of the invention are not enoleic acids and exhibit reduced gastric irritation compared to the unesterified oxicam from which they starch. 15. The term "precursor" refers to compounds which are drug precursors which, after administration and absorption, deliver the drug in vivo through some metabolic process such as hydrolysis.

The invention also includes pharmaceutical compositions suitable for administration to a warm-blooded animal or a human, comprising a pharmaceutically acceptable carrier and an anti-inflation agent, an effective amount of a compound of the formula 1 or 2 cm 2, a method of treating an inflationary condition in a warm-blooded animal in need of such treatment by administering an anti-inflation agent effective amount of a compound of formula 1 or 2.

While all conventional routes of administration can be used with the compounds of the invention, the oral route of administration is preferred.

. After gastrointestinal absorption, the subject compounds are hydrolyzed in vivo to the corresponding oxicams of formula 1 or 2, wherein either are hydrogen or a salt thereof. Since the drug precursors according to the invention are not enolic acids, the exposure of the gastrointestinal tract to the acidic oxicam compounds is thereby reduced to an ammonia. Furthermore, since gastrointestinal complications have been noted as a major adverse reaction of acidic non-steroidal anti-inflammatory drugs (see, e.g., DelFavero in "Side Effects of Drugs Annual T, Dukes and Elis, Eds. Excerpta Medica, Amsterdam, 1983, biz. 104-1051, compounds 1 and 2 of the invention have a clear advantage over the enolic oxicams from which they are derived.

In the process for preparing the new oxicamesters according to the invention, the oxicam of formula 3 or 4 is treated, for example, with at least an equimolar amount of carboxylic acid halide or sulfonyl halide of the formula R ^ X or R ^ X, as indicated in the reaction mixture. . Equations A and B, where R 1, R 3 have the meanings defined above, X is chlorine, bromine or iodine, and B is a suitable standard base. The process is usually carried out in a reaction-inert organic solvent under substantially anhydrous conditions in the presence of 2Q an equivalent amount of suitable standard base. Generally, the reaction is run at 0-50 ° C for 0.5-72 hours, although it is usually most effective to run the reaction at room temperature after reactants are left at a reduced temperature, e.g. 0-10 ° C, 25.

Although any inert organic solvent can be used, it is generally preferred to use a solvent such as an aromatic hydrocarbon, for example benzene, toluene or xylene, a halogenated lower hydrocarbon, for example methylene chloride, chloroform, ethylene dichloride or s-tetrachloroethane; 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;

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8500485-4 or mixtures thereof. Suitable standard bases for use in this process include the alkali and alkaline earth oxides, hydrogen carbonates and carbonates, as well as tertiary amines such as triethylamine; N-irethylpyrrolidine, N-methylmoipholine 5 and pyridine. It should be noted that the standard base used must be present in sufficient amount to neutralize the hydrogen halide formed in the reaction. Most preferably, triethylamine is used as the standard base, because it can be easily removed from the reaction mixture as an insoluble hydrogen halide precipitate.

On the other hand, the compounds of formulas 3 and 4 may be acylated with carboxylic anhydrides in place of the previously defined compounds R x and R x X but which are groups 15 and other groups than said alkyl sulfonyl or benzul sulfony 1. For example, compound 3 and alpha carbonic anhydride, (¾¾) in the presence of any of the aforementioned reaction inert organic solvents, with a molar excess of sodium hydrogen carbonate at room temperature to the corresponding product of formula 1.

The reactions are efficiently monitored by thin layer chromatography, establishing reaction times sufficient to provide a complete reaction, while avoiding unnecessary heating costs and excessive reaction time, which may increase the amount of by-products and yield. drop.

The oxicaraen 3 and 4 required as starting materials can be obtained by methods known in the art, see, for example, the references cited above with respect to oxides. The reagents R X, R X and the above-mentioned corresponding acid anhydrides are commercially available, or are prepared by known methods. The precursor oxides of formulas 1 and 2 are used up

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8500485-5- their anti-inflammatory and analgesic activity evaluated by known methods, such as the rat paw edema test, rat artificially induced arthritis test or mouse phenyl benzoquinone-induced convulsion test, such as those used in the evaluation of the oxicams from which they are derived, and described in the aforementioned references and elsewhere in the literature? see, for example, C.A. Winter, in "Progress in Drug Research." published by E. Jucker, Birkhauser Verlag, Basel, Vol. 10, 1966, 10 pp. 139-192.

In comparison to the oxicams of formulas 3 and 4, from which they originate, the new precursors of formulas 1 and 2 appear to inhibit noticeably less prostagladin synthesis from arachidonic acid in tests performed according to a modification of the method of T. JL Carty et al., Prostaglandins, 19, 51-59 (19801). The modified method uses cultures of rat bascile leukemia cells (REL-11, prepared according to the method of Jakschik et al., Ibid., 16, 733 ( 19781, instead of Rauizenfibroplast 20 (MC5-51 and rabbit synovial cell cultures. Thus, the compounds of the invention are in themselves relatively ineffective as anti-inflammatory agents, but they are converted into an active anti-inflammatory binding agent in hydrolysis in vivo. Since compounds 1 and 2 are not enolic acids, and it is known that hydrolysis takes place, after the precursor leaves the stomach, compounds 1 and 2 significantly reduce gastric irritation, which is caused by oral administration of the enoloxicams they originate from.

The precursor oxicams are generally dosed on a molar basis at the same level and frequency as the known oxicams from which they are derived.

However, the non-enolic nature of the present compounds generally allows for larger tolerated oral doses when such larger dosages are required ·· bathCTU-4 8 5 -6- in the control of pain and inflammation.

The present precursor oxides are also formulated in the same manner, and administered by the same routes as the known oxides, as described in the aforementioned references. The oral route of administration is preferred, making particular use of the non-enolic nature of the present compounds.

The invention is illustrated by the following examples.

Example I

N- (5-Methyl-isoxazol-3-yl-2-methyl-4-henzcyloxy-2H-1,2-benzo- '' thiazine-3-carboxamide-1,1-dioxide 15 (1, = C 8 H 4 CD , R2 = group of formula 5)

2.0 g (6.0 mmoles of N- (5-methylisoxazol-3-yl) -2-ethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (nitrogen) are introduced under a nitrogen atmosphere. isoxicam) together with 35% netharlene diloride! To the resulting bria ren adds 0.92 ml (6.6 nmol) triethylamine, stir the mixture to dissolve and then cool in an ice water bath. A solution of benzoyl chloride, 0.77 ml (6.6 mmoll), in 5 ml of methylene chloride was added dropwise over 5 min. and the mixture was stirred at room temperature overnight. After extracting once with 50 ml of water, twice with 50 ml portions of saturated sodium hydrogen carbonate solution and once with 50 ml of brine, the organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo to a foam.

The foam was rubbed with isopropyl ether, filtered to give 2.15 g of a gray solid, m.p. 203 DEG-25 DEG C. (dec.). This substance was dissolved in 75 ml of hot acetonitrile, the solution was filtered and cooled to room temperature and left overnight under temperature · »

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8500485 -7- obtaining 1.50 g (57.7% 1 beige crystals, melting point 210-212 ° C (dec.)), C21Hlf 6N3S calculated C, 57.40; B, .. 3.90; N , 9.56.

5 GevandenrC, 57.10 .; H, 3.96; N, 9.63.

Infrared spectrum (KBr) ym: 5.7 (ester carbonyl), 5.93 (amide carbonyl), 7.45, 8.55.

Example II

10 N- (5-Methylisaxa2ol-3-yl) -2-methyl-4- (n-hexanoyloxy) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (1, R = CH2 (CH2) 4 <I> = group of formula 5).

The procedure of Example I was repeated, but with n-hexanpyl chloride instead of benzoyl chloride to obtain 2.54 g of crude product which was triturated with 70 ml of isopropyl ether at room temperature and filtered to give 1.84 g of solid dust, mp 142-146 ° C.

After recrystallization from ethanol, 1.08 g of 20 (41.5% 1 colorless crystals, melting point 175-177 ° C (dec.) Were obtained.

For calculated analysis: C, 55.42; H, 5.35; N, 9.69.

Found: C, 55.32; H, 5.52; N, 9.65.

Infrared spectrum (KBrl ym: 5.63 (ester carbonyll, 5.92 (amide carbonyl}), 7.45, 8.45.

Example UI

tl - - (5- (methylisoxazol-3-yl-2-methyl-4- (2,2-dimetdiyl-pentanoyloxy) -2H-1,2-benzothiazine-3-carboxamicle-1,1-dioxide 30 (1, ^ Callback i »Bt fcn« le 5)

By 972 mg (2.90 monol). N-t5-itethylisoxazol-3-yl-2-methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide in 10 ml of ethylene ciloride, 0.45 ml (3.20 mtolL triethyl-oxrrLne and 35 476 mg (3.20 nmoll 2,2-dimethylpentanoic acid chloride in 5 ml bath ^ W4 8 5 -8-.

reacting ethylene chloride according to the method of Example I / reaction mixture twice with 25 ml portions of water, twice with 25 ml saturated sodium hydrogen carbonate solution and extract once with brine, drying the reaction mixture over anhydrous sodium sulfate. and evaporating the solvent, a beige-colored semi-solid was obtained. This substance was triturated with ethyl ether (15 ml), slurried overnight and the resulting mixture was filtered to obtain 1.05 g of off-white solid. The solid was concentrated in hot ethyl acetate (20ml), filtered to remove insoluble matter, and the filtrate cooled to room temperature.

After filtration and air drying, 448.5 mg of colorless crystals, mp 213-215 ° C (34.5% yield), were obtained.

For calculated analysis C, 56.36 * H, 5.63; N, 9.39 Found: C, 5618: H, 5.63; N, 9.41.

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

20 Mass spectra, m / e: 447 (molecular ion).

Example IV

N- (5-Methylisoxazol-3-y 1) - 2-meth.y 1- 4-benzene-sulfonyloxy-2H- 1,2-benzothiazine-3-carboxamide-1,1-dioxide (1, R = 25 CgH ^ SD ^, R2 = group of formula 5)

The procedure of Example 1 was repeated on a 3.0 mmole scale with benzenesulfonyl chloride, instead of benzoyl chloride. After adding the benzenesulfonyl chloride 3Q, a precipitate formed after oxidation for 45 min.

At room temperature. After 60 minutes, the mixture was filtered, the residue was rinsed with a small amount of ethylene chloride to give 0.76 g of a colorless solid, mp 218-220 (dec.). This substance was taken qp in 15 ml of warm aqetonitrile, filtered, and the filtrate / wm 5-9 was cooled to room temperature and left overnight. After filtration and drying, 0.51 g (37%) of colorless crystals, mp 225-226 ° C (anti.), Were obtained.

Analysis calculated for C2q ^ 1 ~ P ^ 2S2: 5 C, 50.521. H, 3.60; N, 8.84.

Found: C, 50.60. H, 3.73; N, 8.83

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

10 Example V

N- (6H3-chloro-2-pyrictyl) - 2-meth.y 1-4-fcenzcylox7-2H-1,2-benzothiazine-3-cai ± oxainide-1,1-dioxide (1, = CgH ^ CD, = group of formula 6) Under a nitrogen atmosphere, 987 mg. (2.70 rrmol) N- (6-chloro-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxyxamide-1,1-dioxide and 15 ml of ethylene chloride brought together . 0.41 ml (2.97 mmol) of triethylamine was added to the resulting suspension and the resulting 20 was obtained. light green solution cooled in an ice water bath and 0.35.

ml (2.97 irmol) benzcyl chloride in 5 ml methylene chloride dripped over three minutes. The resulting mixture was stirred at room temperature overnight, with water (2 x 25 ml), saturated sodium hydrogen carbonate solution (2 x 25 mil, brine (1 x 25 mil) extracted and dried (Na23D ^). By evaporation of the solvent a colorless solid was obtained from the filtrate, which was triturated with isopryl pylether and stirred overnight at room temperature. After filtration and drying of the precipitated product, 1.1 g of colorless solid was obtained, melting point 192-195 ° C. (dec. 1. After recrystallization from hot acetonitrile, 0.72 g (56.7¾ crystals, mp. 195-196 ° C (dec. 1.

Analysis calculated for ^ ^ 22 ^ ^ 5 ^ 013: 35 C, 56.23; H, 3.43; N, 8.94.

BAD8 «3W4 8 5 -10- J *

Found: C; 56.02; H, 3.48? N, 8.93

Infrared spectrum (KBri μΐη: 2.98, 5.70, 5.95, 7.38, 8.4.

Example VI

N- {6-Chloro ^ 2-pyr ± dyll -2-iretliyl-4- (n-hexanoylaxyi -2H-5 1,2-benzothiazine-3-carboxamide-1,1-dioxide (1, R ^ = n- CELL ^ (C1-4 * / R2 = group of formula 61

The procedure of Example V was repeated on a 1.35 nmol scale in 9 ml of methylene chloride using 0.21 ml (1.49 nmol of 1 n-hexancyldiloride) as.

acylating agent in 1 ml of the same solvent. After adding the acid chloride solution in two minutes, the resulting clear yellow solution was stirred at ambient temperature for four hours. stirred, then washed and dried in the usual manner. A yellow gum which crystallized on standing was obtained by evaporating the solvent. These crystals were taken up in 50 ml of isqprcpanol, the mixture was filtered, and the filtrate was left overnight at room temperature to obtain Q, 31 g of 20 (49.5% colorless crystals, mp 154-156 ° C (dec. i.

Analysis Calculated For 5N3CIS: C, 54.37; H, 4.78; N, 9/06.

Found it; C, 54.13; K, 4.91; N, 8.91.

Infrared spectrum (KBri. Jan: 5.65, 5.95, 7.47, 8.5.

25.

example VII

N- (6-Chloro-2-pyri-^ 11-2-methyl-4- (2,2-diitethyl-pentanoyloxyL-2E-1,2-benzothiazxne-3-carbQxaiGide-1,1-dioxide (1, Rj - = CH ^ CH ^ CH ^ C (CH ^ OD, = group of formula 61 30

The procedure of example UI was repeated, but with 1.1 g (3.0 iaraoll N - (6-chloro-2-pyridylL-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxainide-1 1-dioxide as starting material to obtain 1.2 g '(84% 1 crude product, mp 171-173 ° C. After crystallization * from hot ethyl acetate BAI8Wtl ^ 8 5 Λ -11- 0.70 g (49 % 1 colorless solid, mp 171-173 ° C.

For ¢ 22 ^ 2 ^ 51¾ ^ 1 analysis: C, -55.29; H, 5.06; N, 8.79.

Found: C, 55.19, H, 5.08; N, 8.76.

Infrared spectrum (KBr)] ao.i 3.04, 3.38, 5.66, 5.94, 7.35, 8.55.

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

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Example VIII

NH6-Chloro-2-pyridyl) -2-methyl-4-benzenesulfanyl-oxy-2H- 1,2-benzothiazine-3-carboxamide-1,1-dioxide (1, R ^ = CgHgSD2? ^ 2 = 9) mat formula 6) 15

The procedure of Example V was repeated on a 1.26 milliole scale in 9 r @ 1 methylene chloride, acylation with benzenesulfonyl chloride solution. After stirring at room temperature for 4.5 hours, the crude product, as in the previous examples, was recovered, yielding 0.71 g of solid. This material was absorbed.

in 50 ml of hot isopropanol, the mixture is filtered, the filtrate is cooled and the product is collected by filtration and drying in vacuum. 0.33 g (51.8%), mp 190-191 ° C, were obtained.

Analysis Calculated for C 14 H 15 JDg YN Cl: C, 49.85; H, 3.19; N, 8.30 Found: C, 49.75; K, 3.32; N, 8.24.

Infrared spectrum (KBrl Mn: 5.95, 7.4, 8.5.

30

Example IX

N- (2-pyridyl) -2-methyl-4-benzenesulfonyl-y-2H-1,2-thieno {2,3-e} thiazine-3-carboxyld.-1,1-dioxide (2, -R_ - CJ3..SD_) J bo Δ • 35 A mixture of N- (2-pyridyll-2-methyl-4- ΒΑΟφ & ΐΦΚΜ 8 5 -12-hydroxy-2H-1,2-thieno {2,3) was added -e} thiaz: Me-3-C3-baxamide-1,1-dioxide (0.20 g., 0.6 mmol) and 20 ml of methylene diloride under nitrogen atmosphere 0.092 ml * (0.66 mmol) of triethylamine.

0.115 ml (0.9 mol) of 5-benzenesulfonyl chloride was added to the resulting solution, and the mixture was stirred at room temperature for 18 hours. The mixture was washed with sodium hydrogen carbonate solution, brine, dried over Na 2 9D 4 and the solvent 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, mp 175-176 ° C.

Analysis Calculated for C 9 H 15 (DgN 3 S 0.2251 ^ 0: C, 47.94; H, 3.28? N, 8.83; Found: C, 47.70; H, 3.14; N, 9 , 14

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

/

Bfl> 5WL8 5

Claims (8)

A compound characterized in that it has the formula 1 or 2 where (C 1 -C 18) alkanol, benzole, tolycyl, (C 1 -C 18 alkylsulfonyl or benzenesulfonyl), 5-ethylisoxazol-3-yl or 6- is ciloron-2-pyridyl and is benzoyl, tolupyl, 5 (C 1 -C 1) alkylsulfony 1 or benzenesulfonyl. 2. A compound according to claim 1, characterized in that it has the formula 1. Compound according to claim 1, characterized in that it has the formula 2. Compound according to claim 2, characterized in that R 1 (C 2 "C 8) is alkanpyl, benzoyl or benzenesulfonyl. Compound according to claim 4, characterized in that it contains N- (5-methylisoxazol-3-yl) -2-methyl-4-benzoyloxy-2H-1,2-benzophhiazine-3-carboxame-1,1-dioxide , 15 N- (5-roethylisoxazol-3-yl) -2-methyl-4- (n-hexanoyloxyl -2H-1,2-benzothiaziner-3-carboxainide-1,1-dioxide, N- (6-diloorw2) -pyridyll-2-iTethyl-4-benzoyloxy-2H- 1,2-benzothiazine-3-carboxamide-1,1-dioxide, N- (6-daloor-2-pyridyll-2-xrethyl-4- (n-hexanoyl-20 oxy) -2H-1,2-benzothiazine-3-carix-xamide-1,1-dioxide, or N- (6-dxLor-2-pyridyl-2-irethyl-4-benzenesulfanyl-axy-2H-1,2 benzothiazine-3-carboxamide-1,1-dioxide. 6. A compound according to claim 3, characterized in that Rg is benzoyl or benzenesulfonyl. Compound according to claim 6, characterized in that it. N- (2-pyridyl) -2-ethyl-4-benzoyloxy-2K-thieno- {2,3-ê} - 1,2-thiazine-3-carboxamide-1,1-dioxide, or N- (2-pyridyl- 2-methyl-4-benzenesulfonyloxy-2H-30.thieno {2,3-ê} -1,2-thiazine-3-carboxamide-1,1-dioxide. Pharmaceutical preparation with anti-inflammatory action, characterized in that it contains a compound according to claim 1 in a form suitable for administration. ΒΑο8> δι <9ίΑιϊ 8 5