DE3505576A1 - OXICAME ANTI-INFLAMMATORY AND PHARMACEUTICAL COMPOSITIONS CONTAINING SUCH ANTI-PRIME - Google Patents

Description

Pre-active ingredients of anti-inflammatory oxicams and such before pharmaceutical compositions containing active ingredients

The present invention is related to certain ester derivatives of oxicams (1,1-dioxides of N-heteroaryl-4-hydroxy-2-methyl-2H-1, 2-benzothiazine-3-carboxamides and N-heteroaryl-4-hydroxy-2-methyl-2H-thieno / "2,3-e / -1 , 2-thiazine-carboxamiden) deals with the useful oral precursors of these nonsteroidal are anti-inflammatory oxicams.

The oxicams and their utility as anti-inflammatory and analgesic agents are described in U.S. Patents 3,591,584, 3,787,324, 3,822,258, 4,180,662 and 4,376,768. the U.S. Patent 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) analog, which are useful anti-inflammatory agents, in particular for topical administration. J. Med. Chem. J_6_, 44-48 (1973) discloses N-phenyl-4-acetoxy-2-methyl-2H-1,2-benzo-

thiazine-3-carboxamide-i, 1-dioxide as a moderate anti-inflammatory Having activity while the corresponding 4-hydroxy compound had marked activity.

The present invention provides ester anti-inflammatory prodrugs the formula

OR-

COHHR.

or

1 ^J ^ S ^ fS ^ Zy ^ CONH

Γι ι I

I L NCH,

s
/ \

0 0

(ID,

wherein R ₁ is (C ₂ -CG) alkanoyl, benzoyl, toluoyl, _(C1-g) alkylsulfonyl or benzenesulfonyl;

R _{2 is} 5-methylisoxazol-3-yl or 6-chloro-2-pyridyl

and
R ^ benzoyl, toluoyl, (C ₁ -Cg) alkylsulfonyl or benzene

is sulfonyl.

Particularly preferred compounds of the formula (I) are those in which R _{1 is} (C ₂ -C 6) alkanoyl, benzoyl or benzenesulfonyl, and are particularly preferred individual compounds of the formula (I)

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 ^ -benzothiazine-S-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-methy1-4- (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 the formula (II) are those where R 1 is benzoyl or benzenesulfonyl.

The compounds according to the invention are different from the Stamiti oxicams non-enolic acids, and they show reduced gastric irritation when compared to the unesterified parent oxicam.

The term "pre-active ingredient" refers to compounds The drug precursors are those after administration and absorption release the active ingredient in vivo via a metabolic process such as hydrolysis.

The present invention also includes pharmaceutical compositions, suitable for administration to warm blooded animals, including humans, a pharmaceutically acceptable one Carrier and an effective anti-inflammatory amount of a compound of formula (I) or (II), and a A method of treating an inflammatory condition in a warm blooded animal in need of such treatment by Administering an anti-inflammatory effective amount of a compound of formula (I) or (II).

While all of the usual routes of administration for the invention Compounds are useful is the preferred route of administration orally. After gastrointestinal absorption, the compounds of the invention become the corresponding in vivo Oxicams of the formula (I) or (II), in which R ^ or R-J are hydrogen, or a salt thereof are hydrolyzed. Since the pre-active ingredients according to the invention are not enolic acids, the gastrointestinal tract becomes the acidic oxicam compounds so minimally exposed. Furthermore, since gastrointestinal complications are the main adverse reaction of acidic, non-steroidal anti-inflammatory agents have been identified (see e.g. DelFavero in "Side Effects of Drugs Annual 7 ", Dukes and Elis, Eds. Excerpta Medica, Amsterdam, 1983, pp. 104-105) have the invention

Compounds (I) and (II) have a distinct advantage over the enolic parent oxicams.

In the process of making the novel oxicam esters of the invention For example, the parent oxicam of formula (III) or (IV) is added with at least an equimolar amount of a carboxylic acid halide or sulfonyl halide treated as set out below:

halide or sulfonyl halide of the formula RX or R X

CONHR,

+ RX

(I) + EX

(III)

CONH

+ R ³ X

(II) + BX

(IV)

12 "\
wherein R, R and R are as previously defined, X is chlorine, bromine or iodine and B is a suitable standard base. The process is normally carried out in a reaction-inert organic solvent under essentially anhydrous conditions in the presence of an equivalent amount of a suitable standard base. In general, the reaction is carried out at a temperature of from about 0 to about 50 ° C. for a time from about 0.5 to about 72 hours, although it is usually most convenient to carry out the reaction at or about room temperature after the reactants are at Reduced temperature, for example 0 to 10 C, have been brought together.

While any inert organic solvent can 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 one Hydrocarbons, 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 such as methyl acetate, ethyl acetate, isopropyl acetate or methyl propionate, a lower one Dialkyl ethers, e.g. diethyl ether, diisopropyl ether or di-butyl ether, or to use a mixture thereof. Suitable standard basic agents for use in this procedure include the 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 it should be noted that the standard base used must be present in sufficient quantity to absorb the to neutralize released hydrogen halide. Tri-ethylamine is the most preferred standard base since it can easily be removed from the reaction mixture in the form of an insoluble hydrohalide precipitate.

Alternatively, the compounds of formula (III) and (IV) can be acylated with carboxylic acid anhydrides in place of the above compounds R X and RX as defined above, but where R and R are other than the alkylsulfonyl or benzenesulfonyl. For example, the compound (III) and alkylcarboxylic anhydride, (R ) -S> i are reacted in the presence of one of the above, reaction-inert organic solvents with a molar excess of sodium bicarbonate at room temperature to give the corresponding product of the formula (I).

The reactions are conveniently followed by thin layer chromatography, whereby reaction times are determined which are sufficient to deliver full implementation and at the same time avoid unnecessary heating costs and long reaction times, which can increase the content of by-products and decrease yields.

The oxicams (III) and (IV) required as starting materials are obtained according to methods well known in the art available, see e.g. the literature references cited above for oxicams. The above-mentioned reagents R X, R X and the corresponding acid anhydrides are commercially available or are prepared by well known methods.

The oxicam precursors of formula (I) and (II) are on their anti-inflammatory and analgesic activity evaluated according to known methods, such as the rat paw edema test, the adjuvant-induced rat arthritis test or the phenylbenzoquinone-induced writhing test in mice, as used earlier in the evaluation of the Staxnm oxicams and in the above-mentioned references and otherwise described in the literature; see, e.g., C. A. Winter in "Progress in Drug Research" by E. Jucker, Birkhauser Verlag, Basel, Vol. 10, 1966, pp. 139-192.

In comparison with the parent oxicams of the formulas (III) and (IV), it was found that the new pre-active ingredients of the formula (I) and (II) markedly reduced ability to inhibit prostaglandin synthesis from arachidonic acid in tests which according to a modification of the method of T. J. Carty et al., Prostaglandins, 1_9 »51-59 (1980), were carried out. at the modified procedure are cultures of basophilic rat leukemia cells (RBL-1), produced according to the method von Jakschik et al., ibid., χ6, 733 (1978), instead of Mouse fibroblast (MC5-5) and rat synovial cell cultures used. Thus, the compounds of the invention are relatively inactive as anti-inflammatory agents by themselves, but they give an active anti-inflammatory compound after hydrolysis in vivo. Since the compounds (I) and (II) are not enolic Acids are and hydrolysis is known to take place after the prodrug leaves the stomach, they lower those Gastric irritation caused by oral administration of the enolic strain oxicams is considerable.

The oxicam precursors of the present invention are on a molar basis generally dosed in the same amount and frequency as the known oxicams of which they are derive. However, the non-enolic nature of the compounds of the invention generally permits higher tolerated levels oral doses when such higher dosage is required in controlling pain and inflammation.

The oxicam precursors of the present invention are also formulated in the same manner and routes administered as the known oxicams, as described in the publications cited above. The preferred route of administration is oral, which gives particular advantage to the non-enolic nature of the compounds according to the invention is pulled.

The invention is further illustrated by the following examples, but is not limited to the specific details of these examples.

example 1

N- (5-methylisoxazol-3-yl) -r2-methyl-4-benzoyloxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

(I. R ₁ = C ₆ H ₅ CO, R ₂ = II II

Under a nitrogen atmosphere, 2.0 g (6.0 mmol) of N- (5-methylisoxazol-3-yl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1- dioxide (Isoxicam) combined with 35 ml of methylene chloride. To the resulting slurry 0.92 ml (6.6 mmol) of triethylamine are added, the mixture is stirred, doing solution to effect, and then in an ice / Chilled 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.

ΊΟ

After extracting once with 50 ml of water, twice with 50 ml portions of saturated sodium bicarbonate solution and one 50 ml portion of brine was poured over the organic layer dried anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo to a foam. The foam was triturated with isopropyl ether, filtered to give 2.15 g gray solid, m.p. 203-205 C (dec.), to be delivered. This was dissolved in 75 ml of hot acetonitrile, filtered, on Cooled to room temperature and left to stand overnight in order to add 1.50 g (57.7%) of beige crystals, m.p. 210-212 ° C. (decomp.) result.

Analysis for C ₂₁ H ₁₇ OgN ₃ S:

Calcd .: C 57.40 H 3.90 N 9.56
Found: C 57.10 H 3.96 N 9.63

IR spectrum (KBr) around: 5.7 (ester-carbonyl), 5.93 (amide-carbonyl), 7.45, 8.55.

Example 2

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

(I, R ₁ - CH ₃ (CH ₂ J ₄ CO, R ₂ «-, j Jj ₎

The procedure of Example 1 was repeated, but with n-hexanoyl chloride instead of benzoyl chloride to provide 2.54 g 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, melting point 175-177 ° C. (decomp.), Were obtained.

Analysis for

Calc .: C 55.42 H 5.35 N 9.69
Found: C 55.32 H 5.52 N 9.65

IR spectrum (KBr) around: 5.63 (ester-carbonyl), 5.92 (amide-carbonyl), 7.45, 8.45.

Example 3

N- (5-methylisoxazol-3-y1) -2-methyl-4- (2,2-dimethyl-pentanoyloxy) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

(I, R ₁ «CH ₃ CH ₂ CH ₂ C (CH ₃ ) ₂ C0,

CH ₃ ⁾

By reacting 972 mg (2.90 mmol) of N- (5-methyl-isoxazol-3-yl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide in ml of methylene chloride, 0.45 ml (3.20 mmol) of triethylamine, 476 mg (3.20 mmol) of 2,2-dimethylpentanoic acid chloride in 5 ml of methylene chloride Following the procedure of Example 1, extracting the reaction mixture twice with 25 ml portions of water, twice with 25 ml of saturated sodium bicarbonate solution, once with brine, dry over anhydrous sodium sulfate and evaporate of the solvent a beige colored semi-solid was obtained. This was triturated with ethyl ether (15 ml), Slurried overnight and filtered the resulting mixture to give 1.05 g off-white solid. Of the Solid was taken up in hot ethyl acetate (20 ml), filtered to remove insoluble material and the filtrate occurred cooled to room temperature. After filtration and air-drying, 448.5 mg of colorless crystals were obtained, m.p. 213-215 ° C (34.5% yield).

Analysis for C ₂₁ H ₂₅ OgN ₃ S:

Calcd .: C 56.36 H 5.63 N 9.39
Found: C 56.18 H 5.63 N 9.41

IR spectrum (KBr) um: 5.67, 5.88, 6.14, 7.47.8.48. Mass spectrum, m / e: 447 (molecular ion). Example 4

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

(I, R ₁ = C ₆ H ₅ SO ₂ , R ₂ =

The procedure of Example 1 was carried out on a 3.0 millimeter scale repeated with benzenesulfonyl chloride instead of benzoyl chloride. After addition of the benzosulfonyl chloride formed after 45 min stirring at room temperature a precipitate. After 60 minutes the mixture was filtered, with a small amount Methylene chloride was washed to give 0.76 g of a colorless solid, m.p. 218-220 ° C (dec.). This was in 15 ml of warm acetonitrile were taken up, filtered and the filtrate occurred cooled to room temperature and left to stand overnight. After filtering and drying, 0.51 g (37%) became colorless Crystals, m.p. 225-226 ° C (dec.), Were obtained.

Analysis for C ₂₀ H ₁₇ O ₇ N ₃ S ₂ :

Calcd .: C 50.52 H 3.60 N 8.84
Found: C 50.60 H 3.73 N 8.83

IR spectrum (KBr) um: 2.98, 5.95, 7.44-7.55, 8.35-8.60.

Kb

Example 5

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

(I, R ₁ »C ₆ H ₅ CO, R ₂ *

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 Combined 15 ml of methylene chloride. To the resulting suspension was added 0.41 ml (2.97 mmol) of triethylamine, the resulting pale green solution was quenched in an ice / water bath, and 0.35 ml (2.97 mmol) of benzoyl chloride in 5 ml of methylene chloride was passed over 3 min added dropwise. The resulting mixture was stirred at room temperature overnight, extracted with water (2 × 25 ml), saturated sodium bicarbonate solution (2 × 25 ml), brine (1 × 25 ml) and _{dried (over Na 3} SO ₄ ). Evaporation of the solvent from the filtrate gave a colorless solid which was triturated with isopropyl ether and stirred at room temperature overnight. Filtration and drying of the precipitated product gave 1.1 g of colorless solid, melting point 192-195 ° C. (decomp.). Recrystallization from hot acetonitrile gave 0.72 g (56.7%) of crystals, melting point 195-196 ° C. (decomp.).

Analysis for C ₂₂ ^H -i 6 ^ 5 ^N 3 ^C ^ ^S:

calc .: C 56.23 H 3.43 N 8.94
Found: C 56.02 H 3.48 N 8.93

IR spectrum (KBr), pm: 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

(I, R ₁ »n-CH ₃ (CH ₂ ) ₄ " C0, R ₂ »

The procedure of Example 5 was carried out on a 1.35 mmolar 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 repeatedly. After the acid chloride solution had been added over 2 minutes, the resulting solution became clear yellow solution stirred at room temperature for 4 h, then washed in the usual way and dried. Evaporation of the solvent gave a yellow resin which crystallized on standing. This was taken up in 50 ml of isopropanol, filtered and left to stand at room temperature overnight to give 0.31 g (49.5%) of colorless crystals, melting point 154-156 ° C (Decomp.) To deliver.

Analysis for C ₂₁ H ₂₂ O ₅ N ₃ ClS:

Calc .: C 54.37 H 4.78 N 9.06
Found: C 54.13 H 4.91 N 8.91

IR spectrum (KBr) um: 5.65, 5.95, 7.47, 8.5. Example 7

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

(I, R ₁ »CH ₃ CH ₂ CH ₂ C (CH ₃ ) ₂ C0, R ₂ »

The procedure of Example 3 was repeated, but using 1.1 g of (3, OmMoI) N- (6-chloro-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3 -carboxamide-1,1-dioxide as starting material, around 1.2 g (84%) of crude product, melting point 171-173 ° C, to deliver. After crystallization from hot ethyl acetate, 0.70 g (49%) of a colorless solid was obtained. M.p. 171-173 ° C.

Analysis for

Calcd .: C 55.29 H 5.06 N 8.79
Found: C 55.19 H 5.08 N 8.76

IR spectrum (KBr), pm: 3.04, 3.38, 5.66, 5.94, 7.35, 8.55

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

Example 8

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

(I, R ₁ - C ₆ H ₅ SO ₂ ; R ₂

"Φ

The procedure of Example 5 was repeated on a 1.26 mmolar scale in 9 ml of methylene chloride and while acylating with benzenesulfonyl chloride solution. After stirring for 4.5 h
At room temperature 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 and cooled, and the product was collected by filtering and drying in vacuo, 0.33 g (51.8%), melting point 190-191 ° C.

Analysis for C ₂₁ H ₁₆ O ₆ N ₃ S ₃ Cl:

found: C 49.85 H 3.19 N 8.3o
Found: C 49.75 H 3.32 N 8.24

IR spectrum (KBr) um: 5.95, 7.4, 8.5. Example 9

N- (2-pyridyl) -2-methyl-4-benzenesulfonyloxy-2H-1,2-thieno- / 2, S-eythiazine-S-carboxamide-i, 1-dioxide (II, R ₁ = CgH ₅ SO ₃ , R ₂ = 2-pyridyl)

To a mixture of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-thieno / 2,3-e thiazine-3-carboxamid-i, 1-dioxide (0.20 g, 0.6 mmol) in 20 ml of methylene chloride were given 0.092 ml (0.66 mmol) of triethylamine under nitrogen. 0.115 ml (0.9 mmol) of benzenesulfonyl chloride were added to the resulting solution, and the mixture was stirred at room temperature for 18 hours. The mixture was washed with sodium bicarbonate solution, brine, dried (over Na SO.) And the solvent evaporated to give a yellow oil. This was stirred with ethyl ether under nitrogen and the precipitated product collected by filtration and dried in vacuo to give 0,192g (66.9%) of solid, mp. 175-176 ⁰ C, to yield.

Analysis for C ₁ JjH ₁₅ OgN ₃ S ₃ * 0.25 H ₃ O:

Calc .: C 47.94 H 3.28 N 8.83
Found: C 47.70 H 3.14 N 9.14

IR spectrum (KBr) um: 5.91, 7.23, 7.5, 8.3, 8.4, 8.51, 8.61.

Claims (1)

7th January 1985 P.C. (PhRe) 6788 / PDT Claims 1. Compound of formula OR- CONHR or CONH NCH O O / \
0 0 where R ^ (C ₂ -Cg) alkanoyl, benzoyl, toluoyl, (C ₁ -Cg) alkylsulfonyl or benzenesulfonyl, R ₂ 5-methylisoxazol-3 ~ yl or 6-chloro-2-pyridyl and R, benzoyl, toluoyl, ( C ₁ -C) alkyl • j ι 8 is sulfonyl or benzenesulfonyl. 2. Compound of formula CONHR. / \ 0 0 according to claim 1. 3. Compound of formula OR, S / \ 0 0 according to claim 1. 4. A compound according to claim 2, wherein R _{1 is} (C ~ -C _o ) alkanoyl, benzoyl or benzenesulfonyl. 5. Compound according to claim 4, the N- (5-methylisoxazol-3-yl -) - 2-methyl-4-benzoyloxy-2H-1 ₇ 2-benzothiazine-3-carboxamide-1,1-dioxide, N- ( 5-methylisoxazol-3-yl) -2-methyl-4- (nhexanoyloxy) -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-hexanoyloxy) -2H -1,2-Benzothiazine-3-carboxamide-1,1-dioxide or N- (6-chloro-2-pyridyl) -2-methyl-4-benzenesulfonyloxy-2H-1,2-benzothiazine-3-carboxamide-1 , 1-dioxide is. 6. A compound according to claim 3, wherein R _{3 is} benzoyl or benzenesulfonyl. 7. Compound according to claim 6, the N- (2-pyridyl) -2-methyl-4-benzoyloxy-2H-thieno / 2, 3-eJ- ^ , 2-thiazine-3-carboxamide-1,1-dioxide or N- (2-pyridyl) -2-methyl-4-benzenesulfonyloxy-2H-thienO / f2,3-e / -1,2-thiazine-3-carboxamide-1,1-dioxide. 8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-inflammatory effective amount of a compound according to any one of the preceding claims.