JPS6084285A - Crystalline benzothiazine dioxide salt - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention This invention relates to new and useful benzothiazine dioxide salts. More particularly, the present invention describes N-(
The present invention relates to certain novel crystalline non-hygroscopic water-soluble salts of 6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide.

BACKGROUND OF THE INVENTION In the past, various attempts have been made to obtain new and better anti-inflammatory agents. A large part of this is the synthesis and testing of various steroidal compounds such as corticosteroids and acidic nonsteroidal compounds such as phenylbutacin and indomethacin, including the new drug known as piroxicam. . Piroxicam is a member of the anti-inflammatory 4-hydroxy-2H-1,2-benzothiazine-6 family described in U.S. Pat. No. 3,571,584.
- carpoxamide 1,1-dioxide 8, but
In the development of improved anti-inflammatory agents, a need has emerged for anti-arthritic agents that have a high degree of water solubility and other desirable properties, as well as properties that make them suitable for oral, topical or parenteral administration. Published European Patent Application No. 66459A (1
Published December 8, 1982) discloses ethylenediamine, monoethanolamine and jetanolamine salts of piroxicam.

Problems to be Solved by the Invention According to the present invention, N-(6-methyl-2-pyridyl)-
Certain novel non-hygroscopic water-soluble base salts of 2-methyl-4-hydroxy-2H-1,2-benzothiazine-6-carboxamide 1,1-dioxide reduce painful and severe inflammation such as that caused by rheumatoid arthritis. I found it useful to do this. The novel item of the present invention is N7(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2
I(-1,2-benzothiazine-6-carboxamide 1
．． 1-dioxide, an acidic compound of the formula 2, where R is 6-methyl-2-pyridyl.

The novel ethylenediamine, monoethanolamine and jetanolamine salts of the present invention are crystalline and non-hygroscopic;
It dissolves rapidly due to its high water solubility and has excellent chemical and physical stability. These salts are therefore particularly valuable as non-steroidal therapeutics, especially for the treatment of painful inflammation caused by rheumatoid arthritis, and can be used in various dosage forms (for oral, topical or parenteral administration). (including those of ). Jetanolamine salts are the most preferred salts of this invention.

The method used to prepare the novel salts of the present invention includes N-(6-methyl-2-pyridyl)-2-methyl-4
-Hydroxy-2H-1,2-benzothiazine-6-carboxamide 1,1-dioxytone is contacted with at least equimolar amounts of an organic amine base selected from the group consisting of ethylenediamine, monoethanolamine and jetanolamine. This reaction is usually carried out in polar solvents such as water or lower alcohols such as methanol, ethanol or isopropanol, or in methylene chloride,
Chloroform, carbon tetrachloride, ethylene dichloride and S-
It is carried out in a halogenated hydrocarbon solvent such as ethane tetrachloride and the like. Generally, the reaction is conducted at a temperature ranging from about 0°C to about 100°C for about 0.25 to about 1 hour. Once the reaction is complete, the desired salt product can be prepared using conventional methods such as first evaporating the solvent from the reaction mixture and trituring the resulting solid residue or crude concentrated product with a suitable solvent system such as ethyl acetate/chloroform. easily isolated by

Alternatively, appropriate adjustment of the concentration of the aqueous solution of the salt formed in the reaction eliminates the need for isolation.

The starting compounds required for preparing the novel salts of the invention are all known compounds. For example, N-(6-methyl-2
-pyridyl)-2-methyl-4-hydroxy-2H-1
, 2-benzothiazine-3-carboxamide 1,1-dioxide J, G.

Latnbardino U.S. Patent, No. 1S, 591
．． No. 584 and Journal of Medici
nal Chemistry, Vol. 16.

P493 (1973) [these documents describe total syntheses from readily available organic compounds. The amine bases used to prepare the novel amine addition salts of the present invention are all commercially available compounds. -I-1,2-Benzothiazine-6-carboxamide 1,1-dioxide salt can be easily used therapeutically as an anti-arthritic agent. For example, N-
The jetanolamine salt of (6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide is a typical and preferred agent of the invention. It exhibits anti-inflammatory activity in the standard carrageenan-induced rat hindlimb edema test. (
: C, A, Winter et al., Proc, Soc, Ex
p.

11io! , Med, Vol., 111. P544 (1
962)] In this study, 331n9 was administered orally.
Sufficient inhibition of edema was seen at the dose of /klil.

The benzothiazine dioxide salts described herein have further advantages. For example, even if N-(6-methyl-
2-pyridyl)-2-methyl-4-hydroxy-2H-
'1', 2-pentthiazine-6-carboxamide 1.
Even if 1-dioxide itself has very poor water solubility, N-
The jetanolamine salt of (6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2I-f-1,2-benzothiazine-3-carboxamide 1,1-dioxide is easily instantaneous in the above solvent. 3,591,584, the corresponding soluble calcium salt or the anhydrous sodium salt (both of which are soluble in US Pat. No. 3,591,584).
After oral administration, it is absorbed into the bloodstream more quickly than other drugs (prepared by the method described in this issue).

Additionally, this particular salt has a relatively high water temperature level (10 m
9/me) results in a conveniently formulated, stable aqueous solution that is as clear as water. Other salts of the invention give similar results. This means that N-(6-methyl-2-pyridyl)-2-methyl-4,-hydroxy-2I-I-
1,2-benzothiazine-6-carboxamide 1,1-
This is a truly surprising fact since the triethanolamine salt of the dioxide is hygroscopic and difficult to isolate, and the simple ammonium salt is found to be highly unstable when exposed to drying conditions under vacuum. Furthermore, the corresponding sodium salt is also hygroscopic and only slightly soluble in water.

On the other hand, all the novel salts of the present invention are also crystalline, non-hygroscopic solids and can be easily isolated in highly pure crystalline form. These particular properties make these salts particularly suitable for bulk processing into final dosage forms suitable for oral, topical or parenteral administration. Additionally, their plasma half-lives are shorter compared to the corresponding 6-dismethyl analogue (piroxicam), making them more convenient for treating acute conditions such as pain.

The salts described herein can be administered as anti-arthritic agents by any of the routes mentioned above. Generally, these salts will be administered in a dosage range of about 5.0 to about 10,009 doses per day.
However, variations will necessarily occur depending on the weight and condition of the patient being treated and the route of administration chosen. About o,
Dosage levels of 7 days to about 16 kg/ky (body weight) are usually preferred.

It will vary depending on the individual's response to the drug, as well as the type of dosage form and the time interval between doses.

In some cases, dosage levels below the lower end of the above range may be appropriate; in other cases, levels above the range may be used;
Given in smaller doses.

The salts of the present invention, alone or in combination with pharmaceutical carriers, can be administered in a wide variety of dosage forms and by any of the routes mentioned above.

That is, these salts can be used in tablets, capsules, soft and hard lozenges, troches, hard candy-1 powder, sprays, creams, 9F drugs, herbal medicines, sherry, pastes, lotions, ointments, aqueous solutions and suspensions, It can be combined with various pharmaceutical inert carriers in the form of injections, elixirs, syrups, etc.

Such carriers are solid diluents or fillers, sterile aqueous media and non-toxic organic solvents.

Furthermore, the IC1 oral pharmaceutical composition may contain a flavoring agent or flavoring agent as appropriate. Generally, the salts of the invention are present in these dosage forms in concentrations ranging from about 0.5 to about 90 parts by weight.

For oral administration, tablets containing auxiliaries such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be prepared using starch, preferably corn, potato or tapioca starch, alginic acid. and various disintegrants such as certain complex silicates and granulating binders such as hypolyvinylpyrrolidone, gelatin and gum arabic. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in hard gelatin capsules. Lactose and high molecular weight polyethylene glycols are also suitable materials. When aqueous solutions and suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, colorants and, if desired, emulsifying and/or suspending agents such as water, ethanol, It can be mixed with diluents such as propylene glycol, glycerin, and various similar combinations.

For parenteral administration, solutions of these amine salts in sesame oil, peanut oil or aqueous propylene glycol or aqueous ethanol and sterile aqueous solutions in distilled water can be used. Aqueous solutions should be suitably buffered (pH 8) and liquid diluents should be made isotonic. These aqueous solutions are suitable for intravenous injection.

Additionally, the amine addition salts can be administered topically to treat skin and eye irritations in creams, sherry, pastes, ointments, and solutions in standard formulations.

The anti-inflammatory activity of the compounds of the invention is demonstrated in the carrageenan-induced rat hindlimb edema test described above. In this test, anti-inflammatory activity is measured as the inhibition of edema formation in the hind paws of male alpino rats (body weight 150-190.9 mm) produced by injection of carrageenan into the soles.

This drug is usually orally administered in the form of an aqueous solution, and one hour later, 0.05 ml of carrageenan is injected as an aqueous solution.

Edema formation is then determined by measuring the volume of the injected paw initially and 3 hours after carrageenin injection. The increase in volume 3 hours after carrageenan injection is indicative of the individual response. Differences in response between drug-treated animals (6 rats/group) and a control group given vehicle only with standard compounds such as acetylsalicylic acid 100 mf/kfl or phenylbutacin 66, m9/k17 It is considered to be active if the results are significant compared to those obtained by oral administration.

Example 1 450m1 of water 3.0. li' (0,00869 mol) of N-(6-methyl-2-pyridyl)-2-methyl-
4-hydroxy-2,H-1,2-benzothiazine-6
-Carboxamide 1,1-dioxide was added to a well-stirred suspension of 2-560In9 (0,00913 mol).
The amine ethanol was added and the resulting mixture was heated on a steam bath with vigorous stirring for about 5 minutes. The yellow-green solution so obtained was filtered to remove a small amount of water-insoluble material, and the resulting liquid was concentrated in vacuo to a gummy solid. This was triturated with 6 ml of a solvent system of chloroform and ethyl acetate (2:3 by volume) and stirred at room temperature (20°C) overnight under a dry nitrogen atmosphere to obtain a solid precipitate, which was filtered with suction. and dried over phosphorous pentoxide under high vacuum to constant weight. In this way, the final melting point is 1
N-(6-methyl-2-pyridyl)- at 93-195°C
2-methyl-4-hydroxy-2H-1,2-benzothiazine-6-carboxide 1,1-dioxide at 2.9
6 g (844) were obtained. The purified product was further analyzed by infrared spectroscopy and elemental analysis.

Elemental analysis value: Cl8H2□N405S calculated value: C,53,2
0; H, 5,46; N, 13.79 Actual value: C, 52,97; H, 5,46; N, 13.5
1 Example 2 3.0 g (0,00869 mol) N in 450 ml of water
-(6-Methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 960 Da (0,
0096 mol) of jetanolamine was added and the resulting mixture was heated on a steam bath for 5 minutes. The resulting yellow aqueous solution was then filtered to remove some insoluble components.
Obtained: The IP fluid was concentrated in vacuo to give a yellow viscous oil as a residual oil. This oil was treated with a solvent system of 30M chloroform and ethyl acetate (2:6 by volume) and stirred at room temperature (20°C) overnight (16 hours) under a dry nitrogen atmosphere to precipitate yellow crystals. This was subsequently recovered by suction filtration and dried under high vacuum with 5 I'A phosphorous chloride until constant. In this way, the final result is 2.73.
9(704) N-(6-methyl-2-pyridyl)-2
-Crystalline jetanolamine salt of methyl-4-hydroxy-2H-1,2-benzothiazine-6-carpoxamide 1,1-dioxide (melting point 166-167°C)
It's 15. This purified beg was further analyzed by infrared absorption spectroscopy and elemental analysis.

Elemental analysis value: C2o■l2oN, calculated value as 06S: C, 53,
33; H, 5B2; N, 12.44 Actual value: C, 53,00; H, 5,31; N, 12.
41 Example 6 3.0,10.00869 mol) N in 450 m/water
-(6-Methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 550 m9 (0
,00913 mol) of ethylenediamine (0.61 ml
) was added with stirring and the resulting mixture was heated on a steam bath for 5 minutes with continuous vigorous stirring. The hot aqueous solution thus obtained was then filtered to remove small amounts of insoluble components and the resulting P solution was concentrated under vacuum to give a gummy green-yellow oil as a residue. 600m of this residue
A yellow solid was precipitated by trituration with a solvent system of 1 part of ethyl acetate and chloroform (3:2 by volume) and stirring at room temperature (20 °C) overnight (16 hours) in a dry nitrogen atmosphere, which was subsequently was recovered by suction filtration and dried with phosphorus pentoxide under high vacuum to constant weight. In this way, the final K was 2.88 g (82 units) of N-(6-methyl-2-
pyridyl)-2-methyl-4-hydroxy-2H-1,
Purified crystalline ethylenediamine salt of 2-benzothiazine-6-carpoxamide 1,1-dioxide (1% La185
-187°C) was obtained. The purified product was further analyzed by infrared absorption spectroscopy and elemental analysis.

Elemental analysis value: Calculated value as Cl8H23N504S: C, 53, 33
; H, 5, 75; N, 17.27 Actual value: C, 53,
05;
pyridyl)-2-methyl-4-hydroxy-2H-1,
Ethylenediamine salt of 2-benzothiazine-3-carboxamide 1.1-dioxydo 5.88 Microcrystalline cellulose 34.00 Corn starch (United States Pharmacopoeia) 908 Magnesium stearate 1.04 After thoroughly blending the dry compositions, Tablets were compressed from the resulting mixture so that each tablet contained 5 Da of active ingredient.

By using appropriate amounts of the above tablet blend tablets containing 0.25 and 5 omg of active ingredient 'kl respectively! ! ! I left it behind.

Example 5 A dry solid pharmaceutical composition was prepared by blending the following materials in the following weight proportions: N-(6-methyl-2-pyridyl)-2-methyl-4-
Monomethanolamine salt of hydroxy-2H-112-benzothiazine-3-carboxamide 1,1-dioxide 5921 Dicalcium phosphate (anhydrous) 230.10 Corn starch (US Pharmacopeia) 12.50 Sodium lauryl sulfate 0.32 Magnesium stearate 2,87 The dry solid mixture thus produced was thoroughly stirred into a completely homogeneous powder in all respects.

In each case sufficient material was used to make 5 hard gelatin (shoulder 2) capsules containing the above pharmaceutical composition so that each capsule contained 50 Da of active ingredient.

Example 6 N-(6-methyl-2-pyridyl)-2-methyl-4-
Before dissolving the jetanolamine salt of hydroxy-2I (-1,2-benzothiazine-3-carboxamide 1,1-dioxide in propylene glycol), this compound contains 1 part by weight of phosphorus. The appearance was prepared by dissolving it in a mixture of propylene glycol and water (weight ratio 1:4) whose pH was adjusted to 8.0.

The amount of compound used was 57 per i7 g of the solution obtained.
This solution was in such an amount as to contain the active ingredient of n9. sterilized by filtration through a 2 millipore size cellulose membrane. The sterile propylene glycol solution thus obtained is suitable for intramuscular administration to animals.

Example 7 1 part by weight of the monoethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide and 2. An aqueous solution for injection was prepared by first intimately mixing 5 parts by weight of distrium phosphate in a mortar and pestle.

The powder dry mixture thus obtained is then sterilized with ethylene oxide and then aseptically placed into vials and sealed; for intravenous injection, a sufficient amount of distilled water is added to each filled vial before use. A solution containing 10 m9yal of active ingredient per ml of solution for injection is provided.

Example 8 A tablet formulation was prepared by blending materials of the following composition in the following weight ratios: N-(6-methyl-2-
pyridyl)-2-methyl-4-hydroxy-2H-1,
2-Benzothiazine-6-carpoxamide 1,1-dioxide 23.92 Microcrystalline cellulose 311.03 Modified pregelatinized starch N, F, 84.00 Magnesium stearate 0.945 Sodium sulfate 1 Noum 0.105 Above The dry composition was thoroughly blended and the resulting mixture was compressed into tablets, each tablet sized to contain 20 Iv of active ingredient. Other tablets were prepared in a similar manner, each containing 5, 10 and 15 inches of active ingredient per tablet, each using the appropriate amount of tablet blend.

Example 9 A tablet formulation was prepared by using the following materials in the weight proportions of the following composition: N-(6-Methyl-2-pyridyl)-2-methyl-4-
Monoethanolamine salt of hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide 23.69 Dicalcium phosphate (anhydrous) 113.37 Polyvinylpyrrolidone 50.00 Modified pregelatinized starch ( N, F) 10.00 Magnesium Stearate 2.65 Sodium Lauryl Sulfate 0.294 After thoroughly blending the dry composition, the resulting mixture was compressed into tablets so that each tablet contained 20 mg of active ingredient. Similarly, appropriate amounts of each tablet blend were used to obtain 5, 10 and 50 tablets per tablet.
1+lf? Tablets containing 2 active ingredients were prepared.

(5 other people)

Claims (1)

[Claims] +11 N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-
A crystalline non-hygroscopic water-soluble organic amine salt selected from the group consisting of ethylenediamine, monoethanolamine and jetanolamine salts of 3-carboxamide 1,1-dioxide. (2) Claim 1 which is ethylenediamine salt
Compounds described in Section. (3) f# of the patent claim, which is a monoethanolamine salt;
I21i Compound according to item 1. (4) The compound according to claim 1, which is a jetanolamine salt. +51N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2M-1,2-benzothiazine-3
- A composition for treating arthritis comprising a crystalline non-hygroscopic water-soluble organic amine salt selected from the group consisting of ethylenedithymine, monoethanolamine and jetanolamine salts of carboxamide 1,1-dioxide and a pharmaceutically suitable carrier. . (6) The compound is N-(6-methyl-2-pyridyl)-2
The composition according to claim 5, which is a jetanolamine salt of -methyl-4-hydroxy-2H-1,2-benzothiazine-6-carboxyamide 1,1-dioxide.