CA1197845A - Crystalline benzothiazine dioxide salts - Google Patents
Crystalline benzothiazine dioxide saltsInfo
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- CA1197845A CA1197845A CA000462734A CA462734A CA1197845A CA 1197845 A CA1197845 A CA 1197845A CA 000462734 A CA000462734 A CA 000462734A CA 462734 A CA462734 A CA 462734A CA 1197845 A CA1197845 A CA 1197845A
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- methyl
- dioxide
- pyridyl
- hydroxy
- carboxamide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Pharmacology & Pharmacy (AREA)
- Rheumatology (AREA)
- Animal Behavior & Ethology (AREA)
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- Other In-Based Heterocyclic Compounds (AREA)
Abstract
CRYSTALLINE BENZOTHIAZINE DIOXIDE SALTS
Abstract The water-soluble ethylenediamine, monoethanol-amine and diethanolamine salts of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxammide l,l-dioxide have been prepared. These novel crystalline salts are useful in therapy as non-steroidal anti-arthritic agents.
Abstract The water-soluble ethylenediamine, monoethanol-amine and diethanolamine salts of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxammide l,l-dioxide have been prepared. These novel crystalline salts are useful in therapy as non-steroidal anti-arthritic agents.
Description
P.C.(Ph) 6744 CRYSTA~LINE BENZOT~IAZINE DIOXIDE SALTS
This invention relates to new and useful benzothia-zine dioxide salts. More particularly, it is concerned with certain novel crystalline, non-hy~roscopic, water-soluble salts o~ N-(6-methyl-2-pyridyl)-2-methyl-4-hy-droxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide J
which are of especial value in view of their unique com-bination of chemotherapeutic and physical properties.
In the past, various attempts have been made to oktain new and better anti-inflammatoxy a~ents.
For the most part, these efforts have involved the synthesis and testing of various steroidal compounds such as the corticosteroids or non-steroidal substances of an acidic nature such as phenylbutazone, indomethacin and the like, including a new agent known as piroxicam.
The latter substance is a member of a class of anti-in1ammatory 4-hydroxy-2~-1,2-benzothiazine-3-carboxamide l,l-dioxides described and claimed in U.S. Patent No. 3,591,584. However, in the continuing search or improved anti-inflam~atory agents, there is a definite need for anti-arthritic agents having high water-solubility and other desirable properties and especially adapted ~or oral, topical or parenteral administration. In Published European Patent Applica-tion No. 66,459A, publishe~ December 8, 1982, there are disclosed the ethylenediamine, monothanolamine and di-ethanolamine salts of piroxi~am.
4680-2~7 . .
In accordance with the present invention, it has now been found that certain novel crystalline, non-hygroscopic, water-soluble base salts of N-~6-methyl-
This invention relates to new and useful benzothia-zine dioxide salts. More particularly, it is concerned with certain novel crystalline, non-hy~roscopic, water-soluble salts o~ N-(6-methyl-2-pyridyl)-2-methyl-4-hy-droxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide J
which are of especial value in view of their unique com-bination of chemotherapeutic and physical properties.
In the past, various attempts have been made to oktain new and better anti-inflammatoxy a~ents.
For the most part, these efforts have involved the synthesis and testing of various steroidal compounds such as the corticosteroids or non-steroidal substances of an acidic nature such as phenylbutazone, indomethacin and the like, including a new agent known as piroxicam.
The latter substance is a member of a class of anti-in1ammatory 4-hydroxy-2~-1,2-benzothiazine-3-carboxamide l,l-dioxides described and claimed in U.S. Patent No. 3,591,584. However, in the continuing search or improved anti-inflam~atory agents, there is a definite need for anti-arthritic agents having high water-solubility and other desirable properties and especially adapted ~or oral, topical or parenteral administration. In Published European Patent Applica-tion No. 66,459A, publishe~ December 8, 1982, there are disclosed the ethylenediamine, monothanolamine and di-ethanolamine salts of piroxi~am.
4680-2~7 . .
In accordance with the present invention, it has now been found that certain novel crystalline, non-hygroscopic, water-soluble base salts of N-~6-methyl-
2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-
3-carboxamide l,l-dioxide are us~ful as non-steroidal therapeutic agents for alleviating painful inflammatory conditions such as those caused by rheumatoid arthritis, for example. The novel salts of this invention are selected from the group consisting of the ethylenediamine, monoethanolamine and diethanolamine salts of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothia2ine-3-carboxamide l,l-dioxide, which is an acidic compound of the formula:
OH
~CONHR
~N-C~3 wherein R is 6-methyl-2~pyridyl. The novel eth~rlenedi-amine, monoethanolamine and diethanolamine salts of this invention are crystalline, non-hygroscopic, rapidly-dissolving solids with high water solubility and in addition, possess excellent chemical and physical stability. Accordingly, they are particulaxly valuable as non-steroidal therapeutic agents for the treatment or painful inflammatory conditions, especially those caused by rheumatoid arthritis, and are particularly adapted for use in various pharmaceutical dosage forms, including those designed for oral, 2~ topical or parenteral administration. The diethanol-amine sa t is the most preferred salt of this inventicn.
~7~
In accordance with the present invention, thexe is provided a process for preparing a crystalline, non-hygroscopic, water-soluble ethylenediamine, monoethanol-amine or diethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1, l-dioxide, characterized by reacting ~-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3~
carboxamide l,l-dioxide with ethylenediamine, mono-ethanolamine or diethanolamine~ Preferably at least an equivalent amount in moles of the organic amine base i9 used. This reaction is normally carried out in a polar protic ~olvent like water or a lower alkanol such as methanol, ethanol or isopropanol, etc., or in a halogen~
ated hydrocarbon solvent like methylene chloride, chloro-form, carbon tetrachloride, ethylene dichloride and s-tetrachloroethane, etc. In general, the reaction is con-ducted at a temperature that is in the range of from abou~ 20C. up to about 100C. for a period of about 0.2S
to about one hour. Upon completion of the reaction, the desired salt product is easily i~olated in a conven~ional manner, e.g., by first evaporating the solvent from the reaction mixture, followed by tritura-tion Qf the result-ing solid residue or crude concentrate product with a suitable solvent system such as ethyl acetate/chloroform, etc. Alternatively, it is also possible '7~ 5 --4~
to avoid the ne~d for isolation by employing aqueous solutions of the salt as formed ln situ by appropriate adjustment in concentration of the solution.
The starting materials required for preparing the novel salts of this invention are all known compounds.
For instance, N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l~dioxide is described in U.S. Patent No. 3,591,584 to J~ G. Lombardino, as well as in the paper of J. G. Lombardino et al., appearing in the Journal of Medicinal Chemistry, Vol~
16, p. ~93 (1973), including its overall synthesis from readily available organic materials. The amine bases employed to prepare the novel amine addition salts of this invention are all commercially available materials.
T~e N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide salts of the present invention are readily adapted to therapeutic use as anti-arthritic agents. For instance, the diethanolamine salt of N-~6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide, a typical and preferred agent of the present invention, exhibits anti-inflammatory activity in the standard carrageenin-induced rat food edema test [described by C. A. Winter et al., Proc. Soc.
Exp. Biol~ Med., Vol. 111, p. 544 ~1962)], wh~re it was tj found to cause a substantial inhibition in swelling at the 33 mg.~kg. dose level when given by the oral rout~.
The herein descxibed ben~othiazine dioxide salts exhibit additional advantages~ For instance; even th~ugh N-(6-methyl-2~pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide per se is very poorly water-soluble, the diethanolamine salt of N-~6-~ethyl 2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide is readily flash soluble (i.e., instantaneously soluble) in said solvent and therefore should be more rapidly absorbed into the blood stream upon oral administration than the corresponding less soluble calcium salt or even the anhydrous sodium salt of said particular compound ~both of which are prepared according to the procedure already set forth in U.S. Patent No. 3,591,584).
Additionally, this particular salt afords a water-cleax, conveniently formulated stable aqueous solution even at relatively high concentration levels t 10 mg.~l.). The other salts of this invention also afford similar results. This is a truly surprising fact when one considers that the triethanolamine salt of N-~6~methyl-2-pyridyl)-2-methyl-4-hydroxy-2EI-1,2-benzothiazine-3-carboxamide l,l-dioxide is hygroscopic and difficult to isolate and that the simple ammonium salt is found to be highly unstable when subjected to drying conditions under vacuum. Furthermore, the corresponding sodium salt is also hygroscopic and poorly soluble in water. On the other hand, the novel sàlts of this invention are all crystalline, nonh~groscopic solids which are, accordingly, readily isolated in highly pure form. These particular properties further facilitate the bulk processing of said salts into finished pharmaceutical dosage rorms that are especially adapted for use in either oral, topical or parenteral administration, etc. Additionally, their relatively short plasma half-life as compared to the corresponding 6-desmethyl analog (which is piroxicam) affords a still further advantage when treating such acute human disease conditions as pain and the like.
The herein described salts can be administered as anti-arthritic agents by either of the routes previously indicated. In general, these salts will be administered in doses ranging from about 5.0 mg. up to about 1000 m~.
per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen. A dosage level that is in the range o from about 0.08 mg. to about 16 my. per kg of body weight per day is usually preferred, although variations may occur depending upon the individual response to said medicament, lS as wel 1 as on the type of pharmaceutical formulation and the time intervals at which such administration is carried out.
In some instances, dosage levels below the lower limit of the aforesaid range may be adequate, while in other cases higher levels may be employed, divided into several smaller doses for administration throughout the day.
The salts of this invention may be administered alone or in combination with pharmaceutically acceptable carriers by the various routes previously indicated in a wide variety of dosage orms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, soft and hard lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, pastes, lotion~, ointments, aqueous solutions and suspensions, injectable solu~ions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the salts of this inv~ntion are presPnt in such dosage forms at concentration levels ranging from about 0.5~ to about 90~ by weight.
~7-For oral administration, tablets containing various excipien~s such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various dis-integrants such as starch and pref~rably corn, potatoor tapioca starch, al~inic acid and certain c~mplex silicates, together with granulation binders like polyvinylpyrrolidone, gelatin and acacia. Adaitionally, lubricating agents 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 geletin capsules;
preferred materials also include lactose or milk sugar as well as high molecular ~ei~ht polyethylene glycols.
When aqueous solutions and suspensions and/or elixirs are desired for oral administration, the active ingredien~
may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifyin~
and/or suspending agents as well, together with such diluents ~ as water, ethanol, propylene glycol, glycerin and various like combinations thereo~.
For parenteral administration, solutions of these amine salts in sesame or peanut oil or in aqueous propylene glycol or aqueous ethanol may be employed, as well as sterile aqueotls solutions in distilled water~ The aqueous solutions should be suitably buffered (pH 8) and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for in~ra-articular, intramuscular and subcutaneousinjection purposes. Ad~itionally, it is also possible to administer the aforesaid amine addition salts topically when '7~
treating inflammatory conditions of the skin ~r eye by way of creams, jellies, pastes, ointments, solutions and the like, in accordance with standard pharmaceutical practice.
The anti-inflammatory activity of the compounds of the present invention is demonstrated in the previously men~ioned standard carrageenin-induced rat foot edema test. In this test, anti-inflammatory activity is determined as ,he percent inhibition of edema formation in the hind paw of male albino rats (weighing 150-190 g) in response to a sub-plantar injection of carrageenin. The carrageenin is injected as a 1~ aqueous suspension (0.05 ml) one hour after oral administration of the drug, which is normally given in the orm of an aqueous solution. Edema formation is then assessed by measuring the volume of the injected paw initially as well as three hours after the carrageen.in injection. The increase in volume three hours after carrageenin injection constitutes the individual response. Compounds are considered active if the difference in respons~ between the drug-treated animals ~six rats/group) and a cont.ro:l group receiving the vehicle alone is signiicant on comparison with the results afforded by.standard compounds like acetylsalicyclic acid at 100 ~g/kg or phenylbutazone at 33 mg/kg, both by the oral route of administration.
~:~$'7~S
~n9_ To a well-stirred suspension of 3.0 g. (0.00869 mole) of N~(6-methyl-~-pyridyl)-2-methyl-4-hydroxy-~H-1,2-benzothiazine-3-carboxamide l,l-dioxide in 450 ml. of water, S there was added 560 mg. (0.00913 mole) of 2-aminoethanol and the resulting mixture was heated on a steam bath ~with vigorous agitationJ for a period of approximately five minutes. The green-yellow solution so obtained was then filtered to remove a small amount of water insolubles, followed by concentxation of the resulting filtrate ln vacuo to yield a gummy solid. Trituration of the latter material with 300 ml. of a chloroform/ethyl acetate (2:3 by volume) solvent system, followed by stirring at room termperature ( 20~C.) overnight ( 16 hours) under a dry nitrogen atmosphere, then gave a solid pxecipitate which was su~sequently recovered by mea~s of suction filtration and dricd under a high vacuum over phosphorus pentoxide to constant weight. In this manner, there were ultimately obtained 2.96 g. (84%) of the pure crystalline monoetha-nolamine salt of N-~6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide, m.p. 193-195~C. The puxe product was urther character-ized by means of infrared absorption spectra and elemental analysis.
Anal. Calcd. for C ~I N 0 S: C,53:20; H, 5.46;
18 22 ~ 5 N, 13.79. Found: C, 52.97; H, 5.46; N, 13.51.
Example 2 To a suspension of 3.0 g. (O.OOB69 mole) of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide in 450 ml. of water, there was added 9~0 mg. (0.0096 mole) of di~thanolamine and the resulting mixture was heated on a steam bath for a period of five minutes. The yellow aqueous solution so obtained was then filt~ored to remove some insolubles, followed by concentration of the resulting filtrate in vacuo to yield a yellow viscous oil as the residual liquid. Treatment o the latter material with 300 ml.
of a chloroform/ethyl acetate (2:3 by volume~ solvent system, followed by stirring at room temperature ( 20C.) overnight ( 16 hours) under a dry nitrogen atmosphere, then gave a yellow crystalline precipitate which was sub-sequently recovered by ~eans of suction filtration and dried under a high vacuum over phosphorus pentoxide to constant weight. In this manner, there were ultimately obtained 2.73 g. (70%) of the pure crystalline diethanol-amine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide, m.p.
166-167C. The pure product was further characterized by means of infrared absorption spectra and elemental analysis.
Anal. Calcd. for C2 H N40 S: C, 53.33; H, 5.82;
N, 12.44. Found: C, 53.00, H, 5.31; N, 12.41.
mO a suspension of 3.0 g. (0.00869 mole) of N-(6-methyl-2-pyridyl)-2-methyl-4~hydroxy-2H-1,2-ben2Othiazine-3-carboxamide l,l-dioxide in 450 ml. of water, there was added 550 mg. (0.00913 mole) of ethylenediamine (0.61 ml.) with stirring and the resulting mixture was heated on a steam bath (with continued vigorous agitation) for a period of five minutes. The warm aqueous solution so obtained was then filtered to remove a small amount of insolubles, followed by concentration of the result-ing filtrate in vacuo to yield a gummy green-yellow oil as residue. Trituration of the latter material with 300 ml. of an ethyl acetate/chloroform (3:2 by volume) solvent system, followed by stirring at room temperature ( 20C.) overnight ( 16 hours) under a dry nitrogen atmosphere, then gave a yellow solid pre-cipitate which was subsequently recovered by means of suction filtra~ion and dried under a high vacuum over phosphorus p~ntoxide to constant weight. In this manner, there were ultimately obtained 2~88 g. (82%) of the '7~
pure crystalline ethylenediamine salt of N (6-methyl-2-pyridyl)-2-methyl-4-hydroxy~2H-1,2-benzothiazine-3-carboxamide l,l-dioxide, m.p. 185-187C. The pure product was further characterized by means of infrared absorption spectra and elemental analysis.
Anal. Calcd. for C18H23N5O4S: C, 53.33; H, 5.75;
N, 17.27. Found: C, 53.05; H, 5.65; N, 16.92.
Example 4 A dry solid pharmaceutical composition is prepared by blending the following materials together in the proportions by weight specified below:
The ethylenediamine salt of N-(6-methyl-2-pyridyl~-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide....................................... 5.8~
Microcrystalline cellulose................... 34.00 Corn starch, U.S.P...............~........... 9.08 Magnesium stearate..............O............ 1.04 After the dried composition is thorou~hly blended, tablets are punched from the resulting mixture, each tablet being of such a size that it contains 5 mg.
of the active ingredient. Other tablets are also prepared in a similar fashion containing 10, 25 and 50 mg. of the active ingredient, respectively, by merely using the appropriate amount of the tablet blend in each case.
EX~MPLE 5 A dry solid pharmaceutical composition is prepared by combining the following materials together in the pxoportions by weight indicated below:
The monoethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2X-1,2-benzothiazine-3-carboxamide 1,1-dioxide.......................... 59.21 Dicalcium phosphate, anhydrous.. 230.10 3~ Corn starch, U.S.P............. 9 o~ 32~50 Sodium lauryl sulfate O 9 ........... 0.32 Magnesium stearate ~ o~2O87 3~1~S
The dried solid mixture so prepared is then thoroughly agitated so as to obtain a powdered product that is completely uniform in every respect. Hard gelatin (No~2) capsules containing the pharmaceutical composition are then prepared, employing a sufficient quantity of material in each instance so as to provide each capsule with 50 mg.
of the active ingredient.
An aqueous propylene glycol solution containing the diethanolamine salt of N-(5-methyl-2-pyridyl)-2-methyl-4-hydroxy-2~-1,?-benzothiazine-3-carboxamide l,l-dioxide is prepared by dissolving the latter compound in propylene ~lycol-water (1:4 by weight) containing 1~ by weight of trisodium phosphate and adjusted to an apparent pH of 8Ø The amount of compound employed is such that the resultin~ solution contains S m~.
of the active ingredient per each ml. o solution. The solution is then sterilized by means of filtration through a 0.2 m pore size cellulose mem~rane. The sterile aqueous pro~ylene glycol solution so obtained is then suitable for intramuscular administration to animals.
An aqueous injectable solution is prepared by first intimately admixing one part by weight of the monoethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide with 2.5 parts by weight of disodium phosphate with the aid of a mortar and pestle. The ground dry mixture so obtained is then sterilized with ethylene oxide and thereafter aseptically placed into vials and sealed. For purposes of intravenous administration, a ~ufficient amoun. of distilled water is added to each of the filled vials before use so as to ultimately provide a solution which contains 10 mg. of the active ingredient per each ml. of injecta~le solution.
7~ 5 A tablet formulation is prepared by blending the following materials together in the proportions by weight specified below:
The monoethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2~-1,2-benzothiazine-3-carhoxamide 1,1-dioxide....................... ~.... O23.92 Microcrystalline cellulose... ~.... 311.03 Modified pregelatinized starch, N.F.84~00 ~agnesium stearate.............. .. .Ø945 Sodium lauryl sulfate........... .. .Ø105 After the dried composition is thoroughly blende~, tablets are punched from the resulting mixture, each tablet being of such a size that it contains 20 mg. of the active ingredient. Other tablets are also prepared in a similar fashion containing 5, 10 and 50 mg. of the active in~redient, respectively, by merely using the appropriate amount of the tablet blend in each case.
A tablet formulation is prepared by blending the following materials together in the proportions by weight specified below:
The monoethanolamine salt of N-l6-~ethyl-2-pyridyl)-2-methyl~4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide.......................~.......... 23~69 Dicalcium phosphate, anhydrous.............. ll3.37 Polyvinylpyrrolidone......................... 50.00 Modified pregelatini~ed starch, N.F.......... 10.00 Magnesium stearate.................... ~...... 2.65 Sodium lauryl sulfate................. ~...... 0~294 After the dried composition is thoroughly blended, tablets are punched from the resulting mixture, each tablet beiny of such a size that it contains 20 mg. of the active ingredient~ Other tablets a-e also prepared in a ~35 similar fashion containing 5, 10 and 50 mg. o the active ingredient, respectively, by merely using the appropriate amount of the tablet blend in each case.
OH
~CONHR
~N-C~3 wherein R is 6-methyl-2~pyridyl. The novel eth~rlenedi-amine, monoethanolamine and diethanolamine salts of this invention are crystalline, non-hygroscopic, rapidly-dissolving solids with high water solubility and in addition, possess excellent chemical and physical stability. Accordingly, they are particulaxly valuable as non-steroidal therapeutic agents for the treatment or painful inflammatory conditions, especially those caused by rheumatoid arthritis, and are particularly adapted for use in various pharmaceutical dosage forms, including those designed for oral, 2~ topical or parenteral administration. The diethanol-amine sa t is the most preferred salt of this inventicn.
~7~
In accordance with the present invention, thexe is provided a process for preparing a crystalline, non-hygroscopic, water-soluble ethylenediamine, monoethanol-amine or diethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1, l-dioxide, characterized by reacting ~-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3~
carboxamide l,l-dioxide with ethylenediamine, mono-ethanolamine or diethanolamine~ Preferably at least an equivalent amount in moles of the organic amine base i9 used. This reaction is normally carried out in a polar protic ~olvent like water or a lower alkanol such as methanol, ethanol or isopropanol, etc., or in a halogen~
ated hydrocarbon solvent like methylene chloride, chloro-form, carbon tetrachloride, ethylene dichloride and s-tetrachloroethane, etc. In general, the reaction is con-ducted at a temperature that is in the range of from abou~ 20C. up to about 100C. for a period of about 0.2S
to about one hour. Upon completion of the reaction, the desired salt product is easily i~olated in a conven~ional manner, e.g., by first evaporating the solvent from the reaction mixture, followed by tritura-tion Qf the result-ing solid residue or crude concentrate product with a suitable solvent system such as ethyl acetate/chloroform, etc. Alternatively, it is also possible '7~ 5 --4~
to avoid the ne~d for isolation by employing aqueous solutions of the salt as formed ln situ by appropriate adjustment in concentration of the solution.
The starting materials required for preparing the novel salts of this invention are all known compounds.
For instance, N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l~dioxide is described in U.S. Patent No. 3,591,584 to J~ G. Lombardino, as well as in the paper of J. G. Lombardino et al., appearing in the Journal of Medicinal Chemistry, Vol~
16, p. ~93 (1973), including its overall synthesis from readily available organic materials. The amine bases employed to prepare the novel amine addition salts of this invention are all commercially available materials.
T~e N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide salts of the present invention are readily adapted to therapeutic use as anti-arthritic agents. For instance, the diethanolamine salt of N-~6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide, a typical and preferred agent of the present invention, exhibits anti-inflammatory activity in the standard carrageenin-induced rat food edema test [described by C. A. Winter et al., Proc. Soc.
Exp. Biol~ Med., Vol. 111, p. 544 ~1962)], wh~re it was tj found to cause a substantial inhibition in swelling at the 33 mg.~kg. dose level when given by the oral rout~.
The herein descxibed ben~othiazine dioxide salts exhibit additional advantages~ For instance; even th~ugh N-(6-methyl-2~pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide per se is very poorly water-soluble, the diethanolamine salt of N-~6-~ethyl 2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide is readily flash soluble (i.e., instantaneously soluble) in said solvent and therefore should be more rapidly absorbed into the blood stream upon oral administration than the corresponding less soluble calcium salt or even the anhydrous sodium salt of said particular compound ~both of which are prepared according to the procedure already set forth in U.S. Patent No. 3,591,584).
Additionally, this particular salt afords a water-cleax, conveniently formulated stable aqueous solution even at relatively high concentration levels t 10 mg.~l.). The other salts of this invention also afford similar results. This is a truly surprising fact when one considers that the triethanolamine salt of N-~6~methyl-2-pyridyl)-2-methyl-4-hydroxy-2EI-1,2-benzothiazine-3-carboxamide l,l-dioxide is hygroscopic and difficult to isolate and that the simple ammonium salt is found to be highly unstable when subjected to drying conditions under vacuum. Furthermore, the corresponding sodium salt is also hygroscopic and poorly soluble in water. On the other hand, the novel sàlts of this invention are all crystalline, nonh~groscopic solids which are, accordingly, readily isolated in highly pure form. These particular properties further facilitate the bulk processing of said salts into finished pharmaceutical dosage rorms that are especially adapted for use in either oral, topical or parenteral administration, etc. Additionally, their relatively short plasma half-life as compared to the corresponding 6-desmethyl analog (which is piroxicam) affords a still further advantage when treating such acute human disease conditions as pain and the like.
The herein described salts can be administered as anti-arthritic agents by either of the routes previously indicated. In general, these salts will be administered in doses ranging from about 5.0 mg. up to about 1000 m~.
per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen. A dosage level that is in the range o from about 0.08 mg. to about 16 my. per kg of body weight per day is usually preferred, although variations may occur depending upon the individual response to said medicament, lS as wel 1 as on the type of pharmaceutical formulation and the time intervals at which such administration is carried out.
In some instances, dosage levels below the lower limit of the aforesaid range may be adequate, while in other cases higher levels may be employed, divided into several smaller doses for administration throughout the day.
The salts of this invention may be administered alone or in combination with pharmaceutically acceptable carriers by the various routes previously indicated in a wide variety of dosage orms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, soft and hard lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, pastes, lotion~, ointments, aqueous solutions and suspensions, injectable solu~ions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the salts of this inv~ntion are presPnt in such dosage forms at concentration levels ranging from about 0.5~ to about 90~ by weight.
~7-For oral administration, tablets containing various excipien~s such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various dis-integrants such as starch and pref~rably corn, potatoor tapioca starch, al~inic acid and certain c~mplex silicates, together with granulation binders like polyvinylpyrrolidone, gelatin and acacia. Adaitionally, lubricating agents 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 geletin capsules;
preferred materials also include lactose or milk sugar as well as high molecular ~ei~ht polyethylene glycols.
When aqueous solutions and suspensions and/or elixirs are desired for oral administration, the active ingredien~
may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifyin~
and/or suspending agents as well, together with such diluents ~ as water, ethanol, propylene glycol, glycerin and various like combinations thereo~.
For parenteral administration, solutions of these amine salts in sesame or peanut oil or in aqueous propylene glycol or aqueous ethanol may be employed, as well as sterile aqueotls solutions in distilled water~ The aqueous solutions should be suitably buffered (pH 8) and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for in~ra-articular, intramuscular and subcutaneousinjection purposes. Ad~itionally, it is also possible to administer the aforesaid amine addition salts topically when '7~
treating inflammatory conditions of the skin ~r eye by way of creams, jellies, pastes, ointments, solutions and the like, in accordance with standard pharmaceutical practice.
The anti-inflammatory activity of the compounds of the present invention is demonstrated in the previously men~ioned standard carrageenin-induced rat foot edema test. In this test, anti-inflammatory activity is determined as ,he percent inhibition of edema formation in the hind paw of male albino rats (weighing 150-190 g) in response to a sub-plantar injection of carrageenin. The carrageenin is injected as a 1~ aqueous suspension (0.05 ml) one hour after oral administration of the drug, which is normally given in the orm of an aqueous solution. Edema formation is then assessed by measuring the volume of the injected paw initially as well as three hours after the carrageen.in injection. The increase in volume three hours after carrageenin injection constitutes the individual response. Compounds are considered active if the difference in respons~ between the drug-treated animals ~six rats/group) and a cont.ro:l group receiving the vehicle alone is signiicant on comparison with the results afforded by.standard compounds like acetylsalicyclic acid at 100 ~g/kg or phenylbutazone at 33 mg/kg, both by the oral route of administration.
~:~$'7~S
~n9_ To a well-stirred suspension of 3.0 g. (0.00869 mole) of N~(6-methyl-~-pyridyl)-2-methyl-4-hydroxy-~H-1,2-benzothiazine-3-carboxamide l,l-dioxide in 450 ml. of water, S there was added 560 mg. (0.00913 mole) of 2-aminoethanol and the resulting mixture was heated on a steam bath ~with vigorous agitationJ for a period of approximately five minutes. The green-yellow solution so obtained was then filtered to remove a small amount of water insolubles, followed by concentxation of the resulting filtrate ln vacuo to yield a gummy solid. Trituration of the latter material with 300 ml. of a chloroform/ethyl acetate (2:3 by volume) solvent system, followed by stirring at room termperature ( 20~C.) overnight ( 16 hours) under a dry nitrogen atmosphere, then gave a solid pxecipitate which was su~sequently recovered by mea~s of suction filtration and dricd under a high vacuum over phosphorus pentoxide to constant weight. In this manner, there were ultimately obtained 2.96 g. (84%) of the pure crystalline monoetha-nolamine salt of N-~6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide, m.p. 193-195~C. The puxe product was urther character-ized by means of infrared absorption spectra and elemental analysis.
Anal. Calcd. for C ~I N 0 S: C,53:20; H, 5.46;
18 22 ~ 5 N, 13.79. Found: C, 52.97; H, 5.46; N, 13.51.
Example 2 To a suspension of 3.0 g. (O.OOB69 mole) of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide in 450 ml. of water, there was added 9~0 mg. (0.0096 mole) of di~thanolamine and the resulting mixture was heated on a steam bath for a period of five minutes. The yellow aqueous solution so obtained was then filt~ored to remove some insolubles, followed by concentration of the resulting filtrate in vacuo to yield a yellow viscous oil as the residual liquid. Treatment o the latter material with 300 ml.
of a chloroform/ethyl acetate (2:3 by volume~ solvent system, followed by stirring at room temperature ( 20C.) overnight ( 16 hours) under a dry nitrogen atmosphere, then gave a yellow crystalline precipitate which was sub-sequently recovered by ~eans of suction filtration and dried under a high vacuum over phosphorus pentoxide to constant weight. In this manner, there were ultimately obtained 2.73 g. (70%) of the pure crystalline diethanol-amine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide, m.p.
166-167C. The pure product was further characterized by means of infrared absorption spectra and elemental analysis.
Anal. Calcd. for C2 H N40 S: C, 53.33; H, 5.82;
N, 12.44. Found: C, 53.00, H, 5.31; N, 12.41.
mO a suspension of 3.0 g. (0.00869 mole) of N-(6-methyl-2-pyridyl)-2-methyl-4~hydroxy-2H-1,2-ben2Othiazine-3-carboxamide l,l-dioxide in 450 ml. of water, there was added 550 mg. (0.00913 mole) of ethylenediamine (0.61 ml.) with stirring and the resulting mixture was heated on a steam bath (with continued vigorous agitation) for a period of five minutes. The warm aqueous solution so obtained was then filtered to remove a small amount of insolubles, followed by concentration of the result-ing filtrate in vacuo to yield a gummy green-yellow oil as residue. Trituration of the latter material with 300 ml. of an ethyl acetate/chloroform (3:2 by volume) solvent system, followed by stirring at room temperature ( 20C.) overnight ( 16 hours) under a dry nitrogen atmosphere, then gave a yellow solid pre-cipitate which was subsequently recovered by means of suction filtra~ion and dried under a high vacuum over phosphorus p~ntoxide to constant weight. In this manner, there were ultimately obtained 2~88 g. (82%) of the '7~
pure crystalline ethylenediamine salt of N (6-methyl-2-pyridyl)-2-methyl-4-hydroxy~2H-1,2-benzothiazine-3-carboxamide l,l-dioxide, m.p. 185-187C. The pure product was further characterized by means of infrared absorption spectra and elemental analysis.
Anal. Calcd. for C18H23N5O4S: C, 53.33; H, 5.75;
N, 17.27. Found: C, 53.05; H, 5.65; N, 16.92.
Example 4 A dry solid pharmaceutical composition is prepared by blending the following materials together in the proportions by weight specified below:
The ethylenediamine salt of N-(6-methyl-2-pyridyl~-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide....................................... 5.8~
Microcrystalline cellulose................... 34.00 Corn starch, U.S.P...............~........... 9.08 Magnesium stearate..............O............ 1.04 After the dried composition is thorou~hly blended, tablets are punched from the resulting mixture, each tablet being of such a size that it contains 5 mg.
of the active ingredient. Other tablets are also prepared in a similar fashion containing 10, 25 and 50 mg. of the active ingredient, respectively, by merely using the appropriate amount of the tablet blend in each case.
EX~MPLE 5 A dry solid pharmaceutical composition is prepared by combining the following materials together in the pxoportions by weight indicated below:
The monoethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2X-1,2-benzothiazine-3-carboxamide 1,1-dioxide.......................... 59.21 Dicalcium phosphate, anhydrous.. 230.10 3~ Corn starch, U.S.P............. 9 o~ 32~50 Sodium lauryl sulfate O 9 ........... 0.32 Magnesium stearate ~ o~2O87 3~1~S
The dried solid mixture so prepared is then thoroughly agitated so as to obtain a powdered product that is completely uniform in every respect. Hard gelatin (No~2) capsules containing the pharmaceutical composition are then prepared, employing a sufficient quantity of material in each instance so as to provide each capsule with 50 mg.
of the active ingredient.
An aqueous propylene glycol solution containing the diethanolamine salt of N-(5-methyl-2-pyridyl)-2-methyl-4-hydroxy-2~-1,?-benzothiazine-3-carboxamide l,l-dioxide is prepared by dissolving the latter compound in propylene ~lycol-water (1:4 by weight) containing 1~ by weight of trisodium phosphate and adjusted to an apparent pH of 8Ø The amount of compound employed is such that the resultin~ solution contains S m~.
of the active ingredient per each ml. o solution. The solution is then sterilized by means of filtration through a 0.2 m pore size cellulose mem~rane. The sterile aqueous pro~ylene glycol solution so obtained is then suitable for intramuscular administration to animals.
An aqueous injectable solution is prepared by first intimately admixing one part by weight of the monoethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide with 2.5 parts by weight of disodium phosphate with the aid of a mortar and pestle. The ground dry mixture so obtained is then sterilized with ethylene oxide and thereafter aseptically placed into vials and sealed. For purposes of intravenous administration, a ~ufficient amoun. of distilled water is added to each of the filled vials before use so as to ultimately provide a solution which contains 10 mg. of the active ingredient per each ml. of injecta~le solution.
7~ 5 A tablet formulation is prepared by blending the following materials together in the proportions by weight specified below:
The monoethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2~-1,2-benzothiazine-3-carhoxamide 1,1-dioxide....................... ~.... O23.92 Microcrystalline cellulose... ~.... 311.03 Modified pregelatinized starch, N.F.84~00 ~agnesium stearate.............. .. .Ø945 Sodium lauryl sulfate........... .. .Ø105 After the dried composition is thoroughly blende~, tablets are punched from the resulting mixture, each tablet being of such a size that it contains 20 mg. of the active ingredient. Other tablets are also prepared in a similar fashion containing 5, 10 and 50 mg. of the active in~redient, respectively, by merely using the appropriate amount of the tablet blend in each case.
A tablet formulation is prepared by blending the following materials together in the proportions by weight specified below:
The monoethanolamine salt of N-l6-~ethyl-2-pyridyl)-2-methyl~4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide.......................~.......... 23~69 Dicalcium phosphate, anhydrous.............. ll3.37 Polyvinylpyrrolidone......................... 50.00 Modified pregelatini~ed starch, N.F.......... 10.00 Magnesium stearate.................... ~...... 2.65 Sodium lauryl sulfate................. ~...... 0~294 After the dried composition is thoroughly blended, tablets are punched from the resulting mixture, each tablet beiny of such a size that it contains 20 mg. of the active ingredient~ Other tablets a-e also prepared in a ~35 similar fashion containing 5, 10 and 50 mg. o the active ingredient, respectively, by merely using the appropriate amount of the tablet blend in each case.
Claims (13)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a crystalline, non-hygroscopic, water-soluble ethylenediamine, monoethanolamine or diethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1, l-dioxide, characterized by reacting N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide with ethylenediamine, monoethanolamine or diethanolamine.
2. A process for preparing the crystalline, non-hygroscopic,water-soluble ethylenediamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2?-1,2-benzothiazine-3-carboxamide l,l-dioxide, characterized by reacting N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l , l-dioxide with ethylenediamine.
3. A process for preparing the crystalline non-hygroscopic water-soluble monoethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzo-thiazine-3-carboxamide l,l-dioxide, characterized by reacting N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide with monoethanolamine.
4. A process for preparing the crystalline non-hygroscopic, water-soluble diethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-l, 2-benzothiazine-3-carboxamide l,l-dioxide, characterized by reacting N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide with diethanolamine.
5. A process as claimed in claim 1, characterized by the fact that at least an equivalent amount in moles of ethylenediamine, monoethanolamine or diethanolamine is employed with respect to the N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H,1,2-benzothiazine-3-carboxamide l,l-dioxide.
6. A process as claimed in claim 1, characterized by the fact that said reaction is carried out in a polar protic solvent.
7. A process as claimed in claim 3, characterized by the fact that said solvent is water.
8. A process as claimed in claim 1, characterized by the fact that said reaction is carried out in a halogenated hydrocarbon solvent.
9. A process as claimed in claim 5, characterized by the fact that said solvent is methylene chloride.
10. A process as claimed in claim 1, characterized by the fact that said reaction is conducted at a temperature that is in the range of from about 20°C up to about 100°C.
11. The ethylenediamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l, l-dioxide whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.
12. The monoethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.
13. The diethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US53114183A | 1983-09-12 | 1983-09-12 | |
| US531,141 | 1983-09-12 |
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| CA1197845A true CA1197845A (en) | 1985-12-10 |
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| KR (1) | KR850002273A (en) |
| AU (1) | AU546676B2 (en) |
| BE (1) | BE900550A (en) |
| CA (1) | CA1197845A (en) |
| CH (1) | CH660189A5 (en) |
| CS (1) | CS243495B2 (en) |
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| DE (1) | DE3431588A1 (en) |
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| EG (1) | EG16948A (en) |
| ES (1) | ES8506668A1 (en) |
| FI (1) | FI843563L (en) |
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| NL (1) | NL8402768A (en) |
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| NZ (1) | NZ209502A (en) |
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| PL (1) | PL144079B1 (en) |
| PT (1) | PT79178B (en) |
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| FR2818641B1 (en) * | 2000-12-21 | 2004-03-05 | Servier Lab | NOVEL 1,1-DIOXO-2H-1,2-BENZOTHIAZINE 3-CARBOXAMIDES DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
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| US4434164A (en) * | 1981-06-01 | 1984-02-28 | Pfizer Inc. | Crystalline benzothiazine dioxide salts |
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1984
- 1984-08-28 DE DE19843431588 patent/DE3431588A1/en not_active Ceased
- 1984-09-06 GB GB08422487A patent/GB2146328A/en not_active Withdrawn
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- 1984-09-11 KR KR1019840005528A patent/KR850002273A/en not_active Application Discontinuation
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- 1984-09-11 IT IT22603/84A patent/IT1176701B/en active
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