GB2154585A

GB2154585A - Prodrugs of antiinflammatory oxicams

Info

Publication number: GB2154585A
Application number: GB08504355A
Authority: GB
Inventors: Joseph George Lombardino
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 1984-02-23
Filing date: 1985-02-20
Publication date: 1985-09-11
Also published as: SE8500889D0; IT1185514B; FI850742A0; DK81185D0; GB8504355D0; BE901783A; FI850742L; DD232045A5; ZA851317B; ES540590A0; AU552478B2; ES8606312A1; PL252023A1; LU85780A1; NO850725L; PT79988B; KR850006198A; AU3906685A; GR850442B; SE8500889L

Abstract

Novel enol esters of the formula <IMAGE> wherein R1 is an C2-8 alkanoyl, benzoyl, toluoyl, C1-8 alkylsulfonyl or benzene-sulfonyl group; R2 is 5-methylisoxazol-3-yl or 6-chloro-2-pyridyl and R3 is benzoyl, toluoyl, C1-8alkylsulfonyl or benzene sulfonyl; are ### MPW Shell - /s must occur in pairs. useful as prodrug forms of the known unesterified antiinflammatory and analgesic oxicams.

Description

SPECIFICATION Prodrugs of antiinflammatory oxicams The present invention is concerned with 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-2Hthieno[2,3-e]-1,2-thiazine carboxamides) which are useful oral prodrugs of these nonsteroidal antiinflammatory oxicams.

The oxicams and their utility as antiinflammatory and analgesic agents are disclosed in U.S. Patent Nos.

3,591,584; 3,787,324; 3,822,258; 4,180,662 and 4,376,768. U.S. 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 antiinflammatory agents, especiallyfortopical administration. J. Med. Chem., 16,44-48(1973) discloses N-phenyl-4-acetoxy-2-methyl-2H-1,2-benzothiazine-3- carboxamide, dioxide as having moderate antiinflammatory activity while the corresponding 4-hydroxy compound had marked activity.

The present invention provides antiinflammato! y ester prodrugs of the formula

wherein R1 is (C2-C8)alkanoyl, benzoyl,toluoyl, (C,-C8)alkylsulfonyl or benzenesulfonyl; R2 is 5-methylisoxazol-3-yl or 6-chloro-2-pyridyl; and R3 is benzoyl, toluoyl, (C1-C8)alksulfonyl or benzenesulfonyi.

Particularly preferred compounds of formula (I) are those wherein R1 is (C2-C8)alkanoyl, benzoyl or benzenesulfonyl and especially preferred individual compounds of the 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-yI )-2-methyl-4-(n-hexanoyloxy)-2H-l ,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; and N-(6-chlorn-2-pyridyl)-2-methyl-4-benzenesulfonyloxy-2H-1 ,2-benzothiazine-3-carboxamide 1,1-dioxide.

Particularly preferred compounds of formula (II) are those where R3 is benzoyl or benzenesulfonyl.

Unlike the parent oxicams, the invention compounds are not enolic acids and they show reduced gastric irritation when compared with the parent, unesterified oxicam.

The term "prodrug" refers to compounds which are drug precursors which, following administration and absorption, release the drug in vivo via some metabolic process such as hydrolysis.

The present invention also encompasses pharmaceutical compositions suitable for administration to a warm-blooded animal, including a human, which comprises a pharmaceutically acceptable carrier and an antiinflammatory effective amount of a compound of formula (I) or (II), and a method of treating an inflammatory condition in a warm-blooded animal in need of such treatment by administering an antiinflammatory effective amount of a compound of formula (I) or (it).

While all of the usual routes of administration are useful with the invention compounds, the preferred route of administration is oral. After gastrointestinal absorption, the present compounds are hydrolyzed in vivo, to the corresponding oxicams of formula (I) or (II) where R1 or R3 are hydrogen, or a salt thereof. Since the prodrugs of the invention are not enolic acids, exposure of the gastrointestinal tract to the acidic oxicams compound is thereby minimized. Further, since gastrointestinal complications have been noted as a major adverse reaction of acid non-steroidal antiinflammatory drugs [see e.g., DelFavero in "Side Effects of Drugs Annual 7", Dukes and Elis, Eds.Excerpta Medica, Amsterdam, 1983, p. 104-105], the invention compounds (I) and (II) have a distinct advantage over the parent enolic oxicams.

In the process for preparing the novel oxicam esters of the invention the parent oxicam of formula (ill) or (IV) is, for example, treated with at least an equimolar amount of a carboxylic acid halide or sulfonylhalide of the formula R1X or R3X as outlined below:

where R', R2 and R3 are as previously defined, X is chloro, bromo or iodo, and B is an appropriate standard base. The process is normally carried out in a reaction inert organic solvent under substantially an hydrous conditions in the presence of an equivalent amount of an appropriate standard base.In general, the reaction is conducted at a temperature of from about 0"C. up to about 50"C. for a period of from about one-half to about 72 hours, although it is ordinarily most convenient to carry out the reaction at or about room temperature after combining the reactants as 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, methylethyl ketone or methylisobutyl ketone; a lower alkyl ester, e.g., methyl acetate, ethyl acetate, isopropyl acetate or methyl propionate; a lower dialkyl ether, e.g., diethyl ether, diisopropyl ether or di-n-butyl ether; or mixture thereof. Appropriate standard basic agents for use in this process 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 be noted that the standard base employed must be present in sufficient amount to neutralize the liberated hydrogen halide formed in the reaction. Triethylamine is most preferred standard base because 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) may be acylated with carboxylic acid anhydrides in place of the above compounds R'X and R3X as defined above, but where R1 and R3 are other than said alkylsulfonyl or benzenesulfonyl. For example, the compound (Ill) and alkyl carboxylic acid anhydride, (R)2O 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 provide the corresponding product of formula (I).

The reactions are conveniently followed by thin-layer chromatography, thereby determining reaction times sufficient to provide complete reaction and at the same time avoiding unnecessary heating costs and excessive reaction time, which can increase the level of by-products and reduce yields.

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 cited above. The reagents R'X, R3X and the corresponding acid anhydrides noted above are available commercially, or are prepared by well known methods.

The oxicam prodrugs of formula (I) and (II) are evaluated for their antiinflammatory and analgesic activity according to known methods such as the rat foot edema test, rat adjuvant-induced arthritis test or phenylbenzoquinone-induced writhing test in mice, as previously used in the evaluation of the parent oxicams and described in the references cited above and elsewhere in the literature; see e.g., C.A. Winter, in "Progress in Drug Research" edited by E. Jucker, BirkhauserVerlag, Basel, Vol. 10, 1966. pp. 139-192.

In comparison with the parent oxicams of formula (III) and (IV), the novel prodrugs of formula (I) and (II) are found to have markedly reduced ability to inhibit prostagladin synthesis from arachidonic acid in tests carried out by a modification of the method of T. J. Cartyetal., Prostaglandins, 19, 51-59 (1980). In the modified procedure cultures of rat basophilic leukemic cells (RBL-1), prepared by the method of Jakschik et al., ibid., 76,733(1978), are employed in place of mousefibroblast (MC5-5) and rabbit synovial cell cultures.

Thus, the invention compounds themselves are relatively inactive as antiinflammatory agents, but they give rise to an active antiinflammatory compound upon hydrolysis in vivo. Since the compounds (I) and (II) are not enolic acids and it is known that the hydrolysis takes place after the prodrug leaves the stomach, they will significantly reduce the gastric irritation caused by oral administration of the parent enolic oxicams.

On a molar basis, the present oxicam prodrugs are generally 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 higher dosage is required in the control of pain and inflammation.

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

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

EXAMPLE 1 N-(5-Meth yllsoxazoi-3-yI)-2-m eth yI-4-b enzo yloxy-2H- 1, 2-benzo thiazin e-3-carb oxamide 1,7-dioxide fI, R1 = C6i%CO,

Under a nitrogen atmosphere, 2.0 g. (6.0 mmole), N-(5-methylisoxazol-3-yl)-2-methyl-4-hydroxy-2H-1 ,2benzothiazine-3-carboxamide 1,1-dioxide (isoxicam) is combined with 35 ml. methylene chloride. To the resulting slurry is added 0.92 ml. (6.6 mmole) triethylamine, the mixture stirred to effect solution and then cooled in an ice-water bath. A solution of benzoyl chloride, 0.77 ml., (6.6 mmole), in 5 ml. methylene chloride, was added dropwise over five minutes and the mixture stirred at room temperature overnight.After extracting once with 50 ml. water, twice with 50 ml. portions of saturated sodium bicarbonate solution and once with 50 ml. brine, the organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo to afford a foam. The foam was triturated with isopropyl ether, filtered to afford 2.15 g gray solid, M.P. 203-205"C. (dec.). This was dissolved in 75 ml. hot acetonitrile, filtered, cooled to room temperature and allowed to stand overnight to yield 1.50 g. (57.7%) beige crystals, M.P. 210-21 2'C. (dec.).

Analysis Calculated for C2qH1706N3S: C, 57.40; H, 3.90; N, 9.56.

Found: C, 57.10; H, 3.96; N, 9.63.

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

EXAMPLE 2 N-r5-Methylisoxazol-3-ylJ-2-mets7yl-4-{n-hexanoyloxyJ-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (I, R1 = CH3fCH2J4CO,

The procedure of Example 1 was repreated but with n-hexanoyl chloride in place of benzoyl chloride to afford 2.54 g. of crude product which was triturated with 70 ml. 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 were obtained, M.P. 175-177"C. (dec).

Analysis Calculated for C20H2306N3S: C, 55.42; H, 5.35; N, 9.69 Found C, 55.32; H, 5.52; N, 9.65 Infrared spectrum (KBr) microns: 5.63 (ester carbonyl), 5.92 (amide carbonyl), 7.45, 8.45.

EXAMPLE 3 N-{5-Methylisoxazol-3-ylJ-2-methyl-4-f2,2-dimethylpentanoyloxyJ-2H-1,2-benzothiazine-3-carboxamide 1,1dioxide (I, R, = CH3CH2CH2C(CH3J2CO,

By reacting 972 mg (2.90 mmole) N-(5-methylisoxazol-3-yI)-2-methyl-4-hydroxy-2H-1,2-benzothiazine 1,1,-dioxide in 10 ml methylene chloride, 0.45 ml (3.20 mmole) triethylamine, 476 mg (3.20 mmole) 2,2-dimethylpentanoic acid chloride in 5 ml methylene chloride in the procedure of Example 1, extracting the reaction mixture twice with 25 ml portions of water, twice with 26 ml saturated sodium bicarbonate solution, once with brine, drying over anhydrous sodium sulfate and evaporation of solvent afforded a beige colored semisolid.This was triturated with ethyl ether (15 ml), slurred overnight and the resulting mixture filtered to give 1.05 g. of off-white solid. The solid was taken up in hot ethyl acetate (20 ml), filtered to remove insoluble matter, and the filtrate cooled to room temperature. Upon filtration and air drying, 448.5 mg of colorless crystals were obtained, M.P. 213-216C. (34.5% yield).

Analysis Calculated for C21H25O6N3S: C, 56.36; H, 5.63; N, 9.39 Found: C, 56.18; H, 5.63; N, 9.41 Infrared spectrum (KBr) microns: 5.67, 5.88, 6.14,7.47,8.48.

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

EXAMPLE 4 N-85-Methylisoxazol-3-ylJ-2-methyl-4benzenesulfonyloxy-2H-1,2-benzothiazine-3-carboxamide 1, i-dioxide II. R = CGHSSO?, R2 =

The procedure of Example 1 was repeated on a 3.0 mmolar scale with benzenesulfonyl chloride in place of benzoyl chloride. After addition of the benzenesulfonyl chloride a precipitate formed after stirring for 45 minutes at room temperature. After 60 minutes the mixture was filtered, washing with a small amount of methylene chloride to give 0.76 g. colorless solid, M.P. 218-220"C. (dec.). This was taken up in 15 ml. warm acetonitrile, filtered and the filtrate cooled to room temperature and allowed to stand overnight. Upon filtration and drying, 0.51 g. (37%) of colorless crystals were obtained, M.P. 225-226"C. (dec.).

Analysis Calculated for C20H1707N3S2: C, 50.52; H, 3.60; N, 8.84.

Found: C, 50.60; H, 3.73; N, 8.83 Infrared spectrum (KBr) microns: 2.98, 5.95,7.44-7.55, 8.35-8.60.

EXAMPLE 5 N- (6- Chloro-2-p yridyl)-2-m eth yI-4-b enzo yloxy-2H- 1,2-benzothiazine-3-carb oxamide 1,1-dioxide (I, R7 = C6H5CO,

Under a nitrogen atmosphere, was combined 987 mg. (2.70 mmole) N-(6-chloro-2-pyridyl)-2-methyl-4hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide and 15 ml. methylene chloride. To the resulting suspension 0.41 ml. (2.97 mmole) triethylamine was added, the pale green solution obtained was chilled in an ice/water bath and 0.35 ml. (2.97 mmole) benzoylchloride in 5 ml. methylenechloride 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 (Na2SO4).

Evaporation of 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 yielded 0.72 g. (56.7%) of crystals, M.P. 195-196"C. (dec.).

Analysis Calculated for C22H1605N3CIS: C, 56.23; H, 3.43; N, 8.94.

Found: C, 56.02; H, 3.48; N, 8.93 Infrared spectrum (KBr) microns: 2.98, 5.70, 5.95, 7.38,8.4.

EXAMPLE 6 N-6-Chloro-2-pyridylJ-2-methyl-4rn-hexanoyloxy)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide Fl R, = n-CH3fCH2)4CO,

The procedure of Example 5 was repeated on a 1.35 millimolar scale in 9 ml. methylene chloride and employing 0.21 ml. (1.49 mmole) n-hexanoyl chloride as acylating agent in 1 ml. of the same solvent. After adding the acid chloride solution over two minutes, the resulting clear yellow solution was stirred at ambient temperature four hours then washed and dried in the usual manner. Evaporation of solvent gave a yellow gum which crystallized upon standing. This was taken up in 50 ml. isopropanol, filtered, and allowed to stand at room temperature overnight to afford 0.31 g. (49.5%) of colorless crystals, M.P. 154-156"C. (dec.).

Analysis Calculated for C21H2205N3CIS: C, 54.37; H, 4.78; N, 9.06.

Found: C, 54.13; H, 4.91; N, 8.91.

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

EXAMPLE 7 N-66-Chloro-2-pyridyl)-2-methyl-4rZ2-dimethylpentanoyloxy)-2H-1,2-benzothiazine-3-carboxamide 1,1dioxide (I, RI = CH3CH2CH2C{CH3)2CO,

The procedure of Example 3 was repeated but employing 1.1 g. (3.0 mmole) of N-(6-chloro-2-pyridyl)-2 methyl-4-hydroxy-2H-1 ,2-benzothiazine-3-carboxamide 1,1-dioxide as starting material to afford 1.2 g. (84%) of crude product, M.P. 171-1 73"C. Upon crystallization from hot ethyl acetate 0.70 g. (49%) of colorless solid was obtained, M.P. 171-173'C.

Analysis Calculated for C22H2405N3SCI: C, 55.29; H, 5.06; N, 8.7 Found: C, 55.19, H, 5.08; N, 8.76.

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

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

EXAMPLE 8 N-r6-Chloro-2-pyridyl)-2-methyl-4-benzenesulfonyloxy-2H- 1,2-benzothiazine-3-carboxamide dioxide (I, R1 = C6H5S02;

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

Analysis Calculated for C21 H15O6N3S2C1: C, 49.85; H, 3.19; N, 8.30 Found: C, 49.75; H, 3.32; N, 8.24.

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

EXAMPLE 9 N-[2-pyridyl)-2-methyl-4-benzenesulfonyloxy-2H-1,2-thieno[2,3-e]thiazine-3-carboxamide 1,1-dioxide //l, RI = C6H5SO2, R2 = 2-pyridyl) To a mixture of N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1 ,2-thieno[2,3-e]thiazine-3-carboxamide 1,1-dioxide (0.20 g., 0.6 mmole) and 20 ml. methylene chloride was added under nitrogen, 0.092 ml. (0.66 mmole) triethylamine. To the resulting solution was added 0.115 ml. (0.9 mmole) benzenesulfonylchloride and the mixture was stirred at room temperature for 18 hours. The mixture was washed with sodium bicarbonate solution, brine, dried (Na2SO4) and the solvent evaporated to afford a yellow oil. This was stirred with ethyl ether under nitrogen and the precipitated product collected by filtration and dried in vacuo to yield 0.192 g.

(66.9%) of solid, M.P. 175-176 C.

Analysis Calculated for C1H15O6N3S3.0.25H2O: C, 47.94; H, 3.28; N, 8.83 Found: C, 47.70; H, 3.14; N, 9.14.

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

Claims

1. A compound oftheformula

wherein R1 is (CrC8)alkanoyl, benzoyl, toluoyl, (C1-C8)alkylsulfonyl or benzenesulfonyl; R2 is 5methylisoxazol-3-yl or 6-chloro-2-pyridyl; and R3 is benzoyl,toluoyl, (C1-C8)alkylsulfonyl or benzenesulfonyl.

2. A compound of the formula

according to claim 1.

3. A compound of the formula

according to claim 1.

4. A compound according to claim 2 wherein Ri is (C2-C8)alkanoyl, benzoyl or benzenesulfonyl.

5. A compound according to claim 4which is N-(5-methylisoxazol-3-yl)-2-methyl-4-benzoyloxy-2H-1 ,2-benzothiazine-3-carboxamide 1,1-dioxide, N-5-methyl isoxazol-3-yl)-2-methyl-4-(n-hexanoyloxy)-2H-1,2-benzothiazine-3-carboxamide 1,1 -dioxide, N-(6-ch loro-2-pyridyl)-2-methyl-4-benzoyloxy-2-H 1 ,2-benzoth iazine-3-ca rboxa mide 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 dioxide.

6. A compound according to claim 3 wherein R3 is benzoyl or benzenesulfonyl.

7. A compound according to claim 6 which is N-(2-pyridyl)-2-methyl-4-benzoyloxy-2H-thieno-[2,3-ej-1 rboxamide 1,1-dioxide, or N-(2-pyridyl)-2-methyl-4-benzenesu lfonyloxy-2H-thieno[2,3-ej-1 iazi iazi ne-3-carboxamide 1,1-dioxide.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antiinflammatory effective amount of a compound as claimed in any of the preceding claims.

9. A compound as claimed in claim 1 for use in medicine.