CA1177484A - Benzothiazine derivatives - Google Patents
Benzothiazine derivativesInfo
- Publication number
- CA1177484A CA1177484A CA000380804A CA380804A CA1177484A CA 1177484 A CA1177484 A CA 1177484A CA 000380804 A CA000380804 A CA 000380804A CA 380804 A CA380804 A CA 380804A CA 1177484 A CA1177484 A CA 1177484A
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- CA
- Canada
- Prior art keywords
- compound
- benzothiazine
- methyl
- dihydro
- oxo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
Abstract
Abstract of the Disclosure N-(6-halogeno-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides that are novel benzothiazine derivatives. These compounds are characterized by a low degree of toxicity and a low incidence of gastric disorders and useful as anti-inflammatory agents.
Description
~ ~7~48~
Background of the Invention 1) Field of the Invention This invention relates to novel benzothiazine derivatives, a process for the preparation of same, and pharmaceutical compositions (in particular, anti-inflammatory compositions) containing same.
Background of the Invention 1) Field of the Invention This invention relates to novel benzothiazine derivatives, a process for the preparation of same, and pharmaceutical compositions (in particular, anti-inflammatory compositions) containing same.
2) Descript_on of_the Prior Art In the past, aspirin*, fenoprofen and the like were used as anti-inflammatory, analgesic and antipyretic agents.
More recently, indomethacin, diclofenac and t`he like came into common use because of their high anti-inflammatory activity. However, these compounds have such disadvantages as a high degree of toxicity, a high incidence of gastric disorders, a short duration of action, and the like.
Accordingly, Piroxicam ~3,4-dihydro-2-methyl-4-oxo-N~2-pyridyI)--2H~1,2-benzothiazine-3-carboxamide l,l-dioxide]
and Sudoxicam ~3,4-dihydro-2-methyl-4-oxo-N-(2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamlde l,l-dioxide] have been developed as long-acting anti-inflammatory agents of the benzothiazine series ~U.S. Patent 3,591,584). Although these compounds have a potent and long-lasting anti-inflammatory ac-tivity, their high degree of toxicity and high incidence of gastric disorders are not appreciably different from those of indomethacin and diclofenac.
* tr~demark . ~. i~ .
" ~
' Meanwhile, Isoxicam [3,4-dihydro-2-methyl-N-(5-methyl-
More recently, indomethacin, diclofenac and t`he like came into common use because of their high anti-inflammatory activity. However, these compounds have such disadvantages as a high degree of toxicity, a high incidence of gastric disorders, a short duration of action, and the like.
Accordingly, Piroxicam ~3,4-dihydro-2-methyl-4-oxo-N~2-pyridyI)--2H~1,2-benzothiazine-3-carboxamide l,l-dioxide]
and Sudoxicam ~3,4-dihydro-2-methyl-4-oxo-N-(2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamlde l,l-dioxide] have been developed as long-acting anti-inflammatory agents of the benzothiazine series ~U.S. Patent 3,591,584). Although these compounds have a potent and long-lasting anti-inflammatory ac-tivity, their high degree of toxicity and high incidence of gastric disorders are not appreciably different from those of indomethacin and diclofenac.
* tr~demark . ~. i~ .
" ~
' Meanwhile, Isoxicam [3,4-dihydro-2-methyl-N-(5-methyl-
3-isoxazolyl)-4-oxo-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide] has also been developed as an anti-inflammatory agent ~Japanese Patent Laid-Open No. 29373/1972). This compound has an isoxazole structure, so that its degree of toxicity and incidence of gastric disorders are relatively low.
However, its anti-inflammatory activity is lower than that of Piroxicam and Sudoxicam.
Summary of the Invention . _ It is an object of the present invention to provide benzothiazine derivatives which are characterized by a low degree of toxicity and a low incidence of gastric aisorders as well as a potent and long-lasting anti-inflammatory activity.
In accordance with the present invention, there is provided an N-(6-halogeno-2-pyridyl)3,4-dihydro-2-methyl-4-oxo-2H~1,2-benzothiazine-3-carboxamide l,l-dioxide (hereinafter referred to as Compound No. 1) of the formula OH
~ SO `CH3 X (1) where the benzothiazine ring is, for convenience, shown in the enol form with a hydroxyl group at the 4-position but actually exhibits keto-enol tautomerism, and X represents a halogen atom, particularly,a chlorine or fluorine atom.
l 17~48~
The above-defined Compound No. 1 is suitable for use as an anti-inflammatory agent.
Detailed Description of the Invention:
Compound No. 1 can be prepared by heating methyl 3,4-dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate l,l-dioxide ~that is a well-known compound as described in J. Med. Chem., 14, 1171, 1971) and a 2-amino-6-halogenopyridine in xylene to effect condensation thereof. This reaction is preferably carried out by using the reactants in a molar ratio of 1:1 or the 2-amino-6-halogenopyridine in slight excess.
Usually, the reaction temperature is of the order of 100 to 150C and the reaction time is in the range of 2 to 30 hours.
After completion of the reaction, the reaction mixture is coole`d to precipitate and crystallize the desired product.
This product is separated, for example, by filtration and then washed with xylene, alcohol, chloroform or the like to obtain highly pure crystals. The structure of the desired product can be confirmed by elemental analysis, N.M.R.
spectroscopy and the like.
Typical examples of Compound No. 1 include N-~6-chloro-2-pyridylj-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide (hereinafter referred to as Compound No. 1-1) and N-(6-fluoro-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide (hereinafter referred to as Compound No. 1-2). Wi~h respect to anti-inflammatory activity, the duration thereof, the incidence of . . . , ~, .
1 1~7~8d~
gastric disorders, and toxicity ~LD50), these compounds were evaluated as described in Examples 3 to 6 which will be given later. The results thus obtained are summarized in Table 1, so as to permit comparison with control drugs such as Piroxicam, Sudoxicam and Isoxicam, conventional anti-inflammatory agents such as indomethacin and diclo~enac, and well-known analogous compounds such as N-~5-chloro-2-pyridyl)~3,4-dihydro-2-methyl-
However, its anti-inflammatory activity is lower than that of Piroxicam and Sudoxicam.
Summary of the Invention . _ It is an object of the present invention to provide benzothiazine derivatives which are characterized by a low degree of toxicity and a low incidence of gastric aisorders as well as a potent and long-lasting anti-inflammatory activity.
In accordance with the present invention, there is provided an N-(6-halogeno-2-pyridyl)3,4-dihydro-2-methyl-4-oxo-2H~1,2-benzothiazine-3-carboxamide l,l-dioxide (hereinafter referred to as Compound No. 1) of the formula OH
~ SO `CH3 X (1) where the benzothiazine ring is, for convenience, shown in the enol form with a hydroxyl group at the 4-position but actually exhibits keto-enol tautomerism, and X represents a halogen atom, particularly,a chlorine or fluorine atom.
l 17~48~
The above-defined Compound No. 1 is suitable for use as an anti-inflammatory agent.
Detailed Description of the Invention:
Compound No. 1 can be prepared by heating methyl 3,4-dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate l,l-dioxide ~that is a well-known compound as described in J. Med. Chem., 14, 1171, 1971) and a 2-amino-6-halogenopyridine in xylene to effect condensation thereof. This reaction is preferably carried out by using the reactants in a molar ratio of 1:1 or the 2-amino-6-halogenopyridine in slight excess.
Usually, the reaction temperature is of the order of 100 to 150C and the reaction time is in the range of 2 to 30 hours.
After completion of the reaction, the reaction mixture is coole`d to precipitate and crystallize the desired product.
This product is separated, for example, by filtration and then washed with xylene, alcohol, chloroform or the like to obtain highly pure crystals. The structure of the desired product can be confirmed by elemental analysis, N.M.R.
spectroscopy and the like.
Typical examples of Compound No. 1 include N-~6-chloro-2-pyridylj-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide (hereinafter referred to as Compound No. 1-1) and N-(6-fluoro-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide (hereinafter referred to as Compound No. 1-2). Wi~h respect to anti-inflammatory activity, the duration thereof, the incidence of . . . , ~, .
1 1~7~8d~
gastric disorders, and toxicity ~LD50), these compounds were evaluated as described in Examples 3 to 6 which will be given later. The results thus obtained are summarized in Table 1, so as to permit comparison with control drugs such as Piroxicam, Sudoxicam and Isoxicam, conventional anti-inflammatory agents such as indomethacin and diclo~enac, and well-known analogous compounds such as N-~5-chloro-2-pyridyl)~3,4-dihydro-2-methyl-
4-oxo-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide (hereinafter referred to as the 5-chloro-2-pyridyl compound) and N-(6-methyl-2-pyridyl)-3,4-dihydro 2-methyl-4-oxo-2H-benzothiazine-3-carboxamide l,l-dioxide ~hereinafter referred to as the 6-methyl-2-pyridyi compound).
Table l , . .
Anti IGastric Thera- Acut~ Safety inflam- ~dis- peutic toxicity, margin, Test Compound EDtivi~y, ¦UD50 50, 50 LD50 LD50/ED50 ~(mg/k~ m~/k~) - -- ! (mg/kg) of the Compound 6.5 ¦ 200¦ 30.8 ¦ 4,000 615 Invention No 1-2 7.5 29739.6 ! ~5,000 ¦-667 . . .. .
Compounds Piroxicam 1.75 8.2 4.7 490 ' 280 for com- Sudoxicam 5.1 11.8 2.3 500 98 parative purposes Isoxicam 15.5 250 16.1 5,000 322 Indo- 4.6 15.4 i 1.2 17 3.7 methacin I ! ;
¦ Diclo-5,0 ,9.2 ¦ 1.8 ¦420 184 ,I fenac ' I I !
' 5-Chloro-j 2-pyridyl *
, compound 6-Methyl-i 2-pyridyl 4.5 5.1 ~ 1.1 1 - -compound I ~
_ _ ! ! - -1 ~7'~4~4 * When this compound was orally administered in a dose of 6.5 mg/kg, the rate of suppression of edema was found to be as low as 18.9% ~see Table 2). Accordingly, no further tests on this compound were carried out.
** This value is reported in Pharmacometrics, 6(6), 1285 (1972).
*** This value is reported in Folia Pharmacologica Japonica, 6~, 319 (1973).
As can be seen from the data given in Table 1, the benzothiazine derivatives including the compounds of the present invention (Compounds No. 1-l and No. 1-2), Piroxicam, Sudoxicam and Isoxicam are all superior in therapeutic index and safety margin to indomethacin and diclofenac. Among others, the therapeutic index and safety margin of Compounds No. l-l and No. l-2 are remarkably high. When used in clinical applications, therefore, Compounds No~ 1-1 and No. 1-2 are presumed to involve very little risk of producing such side effects (i.e., gastric disorders) as occur frequently as a result of administration of non-steroidal anti-inflammatory agents. Moreover, Compounds No. l-l and No. 1-2 are excellent in the duration of anti-inflam-matory activity as is evident from Table 3 given in Example 4.
It may be understood from the above description that Compounds No. 1-l and No. 1-2 have not only a potent and long-lasting anti-inflammatory activity but also a very high degree of safety.
Depending on the type of symptoms and their sites of I ~7~48~
manifestation, Compounds No. 1-1 and No. 1-2 can be administered in a variety of dosage forms, for example, oral preparations such as tablets, capsules, powders, granules, etc.; suppositories;
liquid preparations; ointments; injectable solutions for intravenous intramuscular and other injection purposes; and the like. However, they are preferably administered in the form of oral preparations or suppositories. Their daily doses for adults can range from 1 to 50 mg and preferably from 5 to 20 mg.
Usually, it is sufficient to administer Compound No. 1-1 or No. 1-2 once a day.
The pharmaceutical compositions of the present invention contain an active ingredient at a concentration of about 10 to 95% and preferably 15 to 90%. They can be prepared by any of well-known conventional techniques such as blending, :
granulation, sugar coating, dissolution and freeze-drying.
For example, pharmaceutical compositions for oral use are prepared by combining an active ingredient with a solid carrier and adding thereto suitable additives as desired. Specifically, sugars, cellulose derivatives, calcium phosphate and the like are used as the carrier, and binders, disintegrants (such as starch), flow controllers, lubricants and the like are used as the additives.
Furthermore, depending on the dosage form, any suitable materials may be incorporated into the pharmaceutical compositions of the present invention.
The present invention is further illustrated by the following examples.
~ ~774~4 Example 1 [Preparation of N-(6-chloro-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide]
~1) Synthesis of 2-amino-6-chloropyridine In a l-litter autoclave were placed 100.6g ~0.68 mole) of 2,6-dichloropyridine and 500 ml of a 29% aqueous ammonia solution. The resulting mixture was heated to 190C and stirred for 5.5 hours. After the mixture was cooled by allowing it to stand overnight, the resulting precipitate was separated by filtration and washed with ice water. Then, the precipitate was dissolved in 500 ml of dichloromethane and the resulting solution was washed with 400 ml of water. The dichloromethane layer was dried over anhydrous sodium sulfate and then concentrated to dryness. Thus, 62.~g of pale-yellow crystals having a melting point of 73C were obtained in a 71.8% yield.
Thin-layer chromatography ~with a solvent system consisting of a 25:1 mixture of CH2C12"and EtoH) gave an Rf value of 0.36.
~2) Synthesis of N-~6-chloro-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide A mixture consisting of 5.38g ~0.02 mole) of methyl 3,4-dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate 1,1-dioxide, 3.86g (0.03 mole) of 2-amino-6-chloropyridine, and 100 ml of xylene was refluxed for 7 hours, during which the methanol formed by this reaction was continuously distilled off.
After the mixture was cooled by allowing it to stand overnight, the resulting precipitate was separated by filtration, washed by stirring it in a 1:1 mixture of warm methanol and chloroform, 1 ~77~8~
collected by filtration, and then dried. Thus, 4.15g of an end product having point of 269-270C (decomp.) was obtained in a 56.7~ yield.
Elemental analysis -- Calcd. for C15H12C~N3O4S ~mol.
wt. 365.791): C, 49.25; H~ 3.31; Cl, 9.69; N, 11.49;
S, 8.46. Found: C, 49.36; H, 3.38; Cl, 9.89; N, 11.66;
S, 8.66.
N.M.R. spectrum (DMSO-d6 solvent, 100C) -- ~=2.84 ~3H, s, N-CH3), 7.34 and 8.0 (7H, m, C6H4 and C5H3N), 9.3 (lH, broad NH), 10.34 (lH, broad OH).
Infrared spectrum (KBr) -- 3305, 1638, 1580, 1530, 1442, 1412, 1360, 1302, 1190, 1170, 1052, 842, 750 cm 1.
Example 2 [Preparation of N-~6-fluoro-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide]
(1) Synthesis of 2-amino-6-fluoropyridine In an autoclave were placed 4.75g of 2,6-difluoro-pyridine and 48 ml of a 29~ aqueous ammonia solution. The resulting mixture was heated to 150C and stirred for 45 minutes.
After the mixture was cooled by allowing it to stand overnight, the resulting precipitate was separated by filtration and washed with ice water. Then, the precipitate was dissolved in 50 ml of dichloromethane and the resulting solution was washed with 40 ml of water. The dichloromethane layer was dried over anhydrous sodium sulfate and then concentrated to dryness. The resulting residue was recrystallized from chloroform-petroleum ~ 1774~4 ether. Thus, 3,4g of crystals having a melting point of 56-58C
were obtained in a 75% yield.
~2) Synthesis of N-(6-fluoro-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide A mixture consisting of 7.68g (0.0285 mole) of methyl 3,4-dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate 1,1-dioxide, 4.8g (0.0428 mole) of 2-amino-6-fluoropyridine, and 29 ml of xylene was refluxed for 17 hours, during which the methanol formed by this reaction was continuously distilled off.
After the mixture was cooled by allowing it to stand overnight, the resulting precipitate was separated by filtration. The filtrate was concentrated and then cooled to obtain an additional precipitate, which was combined with the previously obtained precipitate and washed with hot chloroform. Thus, 7.2g`of crystals`having a melting point of 246-248C (decomp.) were obtained in a 72.3% yield.
Elemental an`alysis -- Calcd. for C15H12FN3O4S (mol. wt.
349.35): C, 51.55; H, 3.46; F, 5.44; N, 12.03; S, 9.18.
Pound: C, 51.69; H, 3.23; F, 5.55; N, 12.29; S~ 9.14.
N.M.R. spectrum (DMSO-d6 solvent) -- ~=2.87 (3H, s, N-CH3), 6.92-7.1 and 7.85-8.2 (7H, m, C6H4 and C5H3N), 10.70 (lH, broad OH).
Example 3 Anti-inflammatory activity was tested as follows:
Male rats of the Wistar strain were used in groups of 7. A ~est compound was suspended in a 0.2% carboxymethyl cellulose solution lL 177~8d~
and orally adminiâtered in a dose of 0.5 ml/100g of body weight.
One hour after administration of the test compound, 0.1 ml of a 1% solution of carrageenin (which is known to be capable of causing inflammation) was âubcutaneously injected into the sole of the right hind leg of each rat. Three hours after injection of carrageenin, each rat was sacrificed by ether. The feet of both hind legs were amputated at the ankle joint and weighed to detect the difference in weight between both feet. Then, the ability of the test compound to suppress the carrageenin-induced edema was evaluated by comparing the foot weight difference of the test group with that of a control group ~consisting of rats to which the solvent alone was administered).
Specifically, the rate of suppression of the edema was calculated according to the following equation:
Rate of Suppression of Edema (%) [Foot Weight Differen e ~g) of Control Group~- [Foot Weight =
[Foot Weight Difference (g) of ifference ~g) of Test Group]
x 100 Control Group]
The results thus obtained are shown in Table 2.
~ ~ 7~8~
Table 2 . . _ . _ . . .
Test Dose Rate of Dose Producing Compound 'm ~k , (~) :0~ Supp~e.sion, Compound No. 1-1 2.0 19.4 6.5 4.0 43.6 8.0 50.6 16.0 71.0 Compound No. 1-2 2.0 20.0 7.5 4.0 32.0 8.0 54.6 16.0 66.6 . _ I . _.___ __ __ _. . _ _ _ ._ !_ . .Piroxicam 0.625 26.9 1.75 . 1.25 42.5 2.5 57.0
Table l , . .
Anti IGastric Thera- Acut~ Safety inflam- ~dis- peutic toxicity, margin, Test Compound EDtivi~y, ¦UD50 50, 50 LD50 LD50/ED50 ~(mg/k~ m~/k~) - -- ! (mg/kg) of the Compound 6.5 ¦ 200¦ 30.8 ¦ 4,000 615 Invention No 1-2 7.5 29739.6 ! ~5,000 ¦-667 . . .. .
Compounds Piroxicam 1.75 8.2 4.7 490 ' 280 for com- Sudoxicam 5.1 11.8 2.3 500 98 parative purposes Isoxicam 15.5 250 16.1 5,000 322 Indo- 4.6 15.4 i 1.2 17 3.7 methacin I ! ;
¦ Diclo-5,0 ,9.2 ¦ 1.8 ¦420 184 ,I fenac ' I I !
' 5-Chloro-j 2-pyridyl *
, compound 6-Methyl-i 2-pyridyl 4.5 5.1 ~ 1.1 1 - -compound I ~
_ _ ! ! - -1 ~7'~4~4 * When this compound was orally administered in a dose of 6.5 mg/kg, the rate of suppression of edema was found to be as low as 18.9% ~see Table 2). Accordingly, no further tests on this compound were carried out.
** This value is reported in Pharmacometrics, 6(6), 1285 (1972).
*** This value is reported in Folia Pharmacologica Japonica, 6~, 319 (1973).
As can be seen from the data given in Table 1, the benzothiazine derivatives including the compounds of the present invention (Compounds No. 1-l and No. 1-2), Piroxicam, Sudoxicam and Isoxicam are all superior in therapeutic index and safety margin to indomethacin and diclofenac. Among others, the therapeutic index and safety margin of Compounds No. l-l and No. l-2 are remarkably high. When used in clinical applications, therefore, Compounds No~ 1-1 and No. 1-2 are presumed to involve very little risk of producing such side effects (i.e., gastric disorders) as occur frequently as a result of administration of non-steroidal anti-inflammatory agents. Moreover, Compounds No. l-l and No. 1-2 are excellent in the duration of anti-inflam-matory activity as is evident from Table 3 given in Example 4.
It may be understood from the above description that Compounds No. 1-l and No. 1-2 have not only a potent and long-lasting anti-inflammatory activity but also a very high degree of safety.
Depending on the type of symptoms and their sites of I ~7~48~
manifestation, Compounds No. 1-1 and No. 1-2 can be administered in a variety of dosage forms, for example, oral preparations such as tablets, capsules, powders, granules, etc.; suppositories;
liquid preparations; ointments; injectable solutions for intravenous intramuscular and other injection purposes; and the like. However, they are preferably administered in the form of oral preparations or suppositories. Their daily doses for adults can range from 1 to 50 mg and preferably from 5 to 20 mg.
Usually, it is sufficient to administer Compound No. 1-1 or No. 1-2 once a day.
The pharmaceutical compositions of the present invention contain an active ingredient at a concentration of about 10 to 95% and preferably 15 to 90%. They can be prepared by any of well-known conventional techniques such as blending, :
granulation, sugar coating, dissolution and freeze-drying.
For example, pharmaceutical compositions for oral use are prepared by combining an active ingredient with a solid carrier and adding thereto suitable additives as desired. Specifically, sugars, cellulose derivatives, calcium phosphate and the like are used as the carrier, and binders, disintegrants (such as starch), flow controllers, lubricants and the like are used as the additives.
Furthermore, depending on the dosage form, any suitable materials may be incorporated into the pharmaceutical compositions of the present invention.
The present invention is further illustrated by the following examples.
~ ~774~4 Example 1 [Preparation of N-(6-chloro-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide]
~1) Synthesis of 2-amino-6-chloropyridine In a l-litter autoclave were placed 100.6g ~0.68 mole) of 2,6-dichloropyridine and 500 ml of a 29% aqueous ammonia solution. The resulting mixture was heated to 190C and stirred for 5.5 hours. After the mixture was cooled by allowing it to stand overnight, the resulting precipitate was separated by filtration and washed with ice water. Then, the precipitate was dissolved in 500 ml of dichloromethane and the resulting solution was washed with 400 ml of water. The dichloromethane layer was dried over anhydrous sodium sulfate and then concentrated to dryness. Thus, 62.~g of pale-yellow crystals having a melting point of 73C were obtained in a 71.8% yield.
Thin-layer chromatography ~with a solvent system consisting of a 25:1 mixture of CH2C12"and EtoH) gave an Rf value of 0.36.
~2) Synthesis of N-~6-chloro-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide A mixture consisting of 5.38g ~0.02 mole) of methyl 3,4-dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate 1,1-dioxide, 3.86g (0.03 mole) of 2-amino-6-chloropyridine, and 100 ml of xylene was refluxed for 7 hours, during which the methanol formed by this reaction was continuously distilled off.
After the mixture was cooled by allowing it to stand overnight, the resulting precipitate was separated by filtration, washed by stirring it in a 1:1 mixture of warm methanol and chloroform, 1 ~77~8~
collected by filtration, and then dried. Thus, 4.15g of an end product having point of 269-270C (decomp.) was obtained in a 56.7~ yield.
Elemental analysis -- Calcd. for C15H12C~N3O4S ~mol.
wt. 365.791): C, 49.25; H~ 3.31; Cl, 9.69; N, 11.49;
S, 8.46. Found: C, 49.36; H, 3.38; Cl, 9.89; N, 11.66;
S, 8.66.
N.M.R. spectrum (DMSO-d6 solvent, 100C) -- ~=2.84 ~3H, s, N-CH3), 7.34 and 8.0 (7H, m, C6H4 and C5H3N), 9.3 (lH, broad NH), 10.34 (lH, broad OH).
Infrared spectrum (KBr) -- 3305, 1638, 1580, 1530, 1442, 1412, 1360, 1302, 1190, 1170, 1052, 842, 750 cm 1.
Example 2 [Preparation of N-~6-fluoro-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide]
(1) Synthesis of 2-amino-6-fluoropyridine In an autoclave were placed 4.75g of 2,6-difluoro-pyridine and 48 ml of a 29~ aqueous ammonia solution. The resulting mixture was heated to 150C and stirred for 45 minutes.
After the mixture was cooled by allowing it to stand overnight, the resulting precipitate was separated by filtration and washed with ice water. Then, the precipitate was dissolved in 50 ml of dichloromethane and the resulting solution was washed with 40 ml of water. The dichloromethane layer was dried over anhydrous sodium sulfate and then concentrated to dryness. The resulting residue was recrystallized from chloroform-petroleum ~ 1774~4 ether. Thus, 3,4g of crystals having a melting point of 56-58C
were obtained in a 75% yield.
~2) Synthesis of N-(6-fluoro-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide A mixture consisting of 7.68g (0.0285 mole) of methyl 3,4-dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate 1,1-dioxide, 4.8g (0.0428 mole) of 2-amino-6-fluoropyridine, and 29 ml of xylene was refluxed for 17 hours, during which the methanol formed by this reaction was continuously distilled off.
After the mixture was cooled by allowing it to stand overnight, the resulting precipitate was separated by filtration. The filtrate was concentrated and then cooled to obtain an additional precipitate, which was combined with the previously obtained precipitate and washed with hot chloroform. Thus, 7.2g`of crystals`having a melting point of 246-248C (decomp.) were obtained in a 72.3% yield.
Elemental an`alysis -- Calcd. for C15H12FN3O4S (mol. wt.
349.35): C, 51.55; H, 3.46; F, 5.44; N, 12.03; S, 9.18.
Pound: C, 51.69; H, 3.23; F, 5.55; N, 12.29; S~ 9.14.
N.M.R. spectrum (DMSO-d6 solvent) -- ~=2.87 (3H, s, N-CH3), 6.92-7.1 and 7.85-8.2 (7H, m, C6H4 and C5H3N), 10.70 (lH, broad OH).
Example 3 Anti-inflammatory activity was tested as follows:
Male rats of the Wistar strain were used in groups of 7. A ~est compound was suspended in a 0.2% carboxymethyl cellulose solution lL 177~8d~
and orally adminiâtered in a dose of 0.5 ml/100g of body weight.
One hour after administration of the test compound, 0.1 ml of a 1% solution of carrageenin (which is known to be capable of causing inflammation) was âubcutaneously injected into the sole of the right hind leg of each rat. Three hours after injection of carrageenin, each rat was sacrificed by ether. The feet of both hind legs were amputated at the ankle joint and weighed to detect the difference in weight between both feet. Then, the ability of the test compound to suppress the carrageenin-induced edema was evaluated by comparing the foot weight difference of the test group with that of a control group ~consisting of rats to which the solvent alone was administered).
Specifically, the rate of suppression of the edema was calculated according to the following equation:
Rate of Suppression of Edema (%) [Foot Weight Differen e ~g) of Control Group~- [Foot Weight =
[Foot Weight Difference (g) of ifference ~g) of Test Group]
x 100 Control Group]
The results thus obtained are shown in Table 2.
~ ~ 7~8~
Table 2 . . _ . _ . . .
Test Dose Rate of Dose Producing Compound 'm ~k , (~) :0~ Supp~e.sion, Compound No. 1-1 2.0 19.4 6.5 4.0 43.6 8.0 50.6 16.0 71.0 Compound No. 1-2 2.0 20.0 7.5 4.0 32.0 8.0 54.6 16.0 66.6 . _ I . _.___ __ __ _. . _ _ _ ._ !_ . .Piroxicam 0.625 26.9 1.75 . 1.25 42.5 2.5 57.0
5.0 76.4 Sudoxicam 1.25 14.9 5.1 2.5 30.7 5.0 45.5 10.0 69.3 Isoxicam 73 575 32 3 15.5 15.0 46.8 30.0 69.4 Indomethacin `1.25 19.3 4.6 2.5 22.8 5.0 57.4 10.0 73.3 Diclofenac 2.5 29.7 5.0 5.0 48.5 10.0 69.3 5-Chloro-2- 6.5 18.9 pyridyl compound
6-Methyl-2- 1.75 27.4 4.5 pyridyl 6.5 58.9 compound _ , _ .
, 1 1774~
Example 4 .
The duration of anti-inflammatory activity was tested as follows: Employing ED50 values determined in Example 3, the duration of anti-inflammatory activity was examined by varying the premedication time. The premedication time was defined as the time interval between the administration of a test compound and the injection of carrageenin. Tests were carried out in substantially the same manner as described in Example 3. The results thus obtained are shown in Table 3.
Tab'le 3 .. . , . ... _ _ . _ . . .
Rate of Suppresion of Edem`a (%) in Rats Premedi~ ,ation at Vario us Times _ 1 hr. 3 hrs. 6 hrs. 12'hrs, 24 hrs. 48 hrs .
. __ . ~ ., . __ . . .
Compound No. 1-1 55.7 54.9 48.3 40.322.6 9.8 Compound No. 1 2 56.6 54.8 43.2 39.120.7 3.4 .,,,_ ... . .. . _ . . ,. .
Piroxicam 57.6 55.3 40.0 38.815.3 1.7 Sudoxicam 49.8 52.1 39.5 31.610.4 -2.4 Isoxicam 54.2 54.2 45.8 36.319.5 1.1 Indomethacin 49.4 57.6 29.4 18.8-3.5 Diclofenac 45.9 24.7 17.6 11.8-1.2 Ex-amp'l-e' 5 The incidence of gastric disorders in rats was 'tested as follows:~ Eight~weeks-old male rats of the Wistar strain were used in groups of 5 to 7. After they were fasted ~ . - , " , .. . .
", .''','' " ." ' .
1 ~774~
for 18 hours or more, a test compound was administered orally.
Six hours later, each rat was sacrificed by decapitation.
The stomach was removed, filled with 10 ml of physiological saline, and then fixed in 5% formalin. After about 10 minutes, the stomach was incised through the greater curvature and the presence or absence of gastric disorders (in particular, erosion) was examined by visual observation. According to Litchfield~Wilcoxon's method, the dose causing erosion to occur in 50~ of the test animals, UD50, was calculated on an all-or-none basis. The results thus obtained are shown in Table 4.
Table 4 . . . .
. . . . . . .. , _ . . _ ., _ .
.Test Compound UDso (mg/kg, P ) Compound No. 1~1 200 Compound No. 1^2 297 .... _ .. _ .. - ... .
Piroxicam 8.2 Sudoxicam 11.8 Isoxicam 250 Indomethacin 5.4 Diclofenac 9.2 6~ethyl-2-pyridyl 5.1 ~ compound _ .
Example 6 Acute toxicity was tested as follows: Male mice of the ddY strain were used in groups of 5. A test compound was 4 8 ~1 suspended in a 0.2% carboxymethyl cellulose solution and orally administered in a dose of 0.1 ml/lOg of body weight. Thereafter, the animals were observed for 7 days. The LD50 value was calculated on the ~asis of the death rates on the final day.
The results thus obtained are shown in Table 5.
Table 5 .
.... _ . . . .. ... _ . . . ........ . . .. , ., . .. ~
Dose Number of Deaths/ LD
Test Compound (mg/kg, p.o.) Total Numb r of (mg/kg, p.o.) Compound No. 1~1 1,000 0/5 4,000 3,000 2/5 5,000 3/5 Compound No. 1-2 3,000 0/5 4,000 0/5>5,000 5,000 0/5 . . _. .... .. ....
Piroxicam ~100 0/5490 Sudoxicam 200 0/5500 1,000 5/5 Isoxicam 3,000 0/55,000 4,000 1/5 ' 5~000 3/5 __ .
.. . .
~~xa'mp-l'e' 7 .. . ..
Tablets containing Compound No. 1-1 were prepared according to the following recipe:
. . .
~ 177~8~ -Compound No. 1-1 10 mg Corn starch 270 mg Polyvinyl pyrrolidone15 mg Magnesium stearate 5 mg Using a tablet machine, the above ingredients were blended and compressed into a tablet.
E-xamp'l'e` 8 Capsules containing Compound No. l-l were prepared according to the ~ollowing recipe:
Compound No. l-l 10 mg Corn starch 230 mg Lactose 50 mg ~agnesium stearate 10 mg The`above ingredients were blended and enclosed in a hard gelatin shell.
E`~am'ple 9 Suppositories containing Compound No. l-l were prepared by suspending 20 mg of finely powdered Compound No. l-l in 5 ml of O.D.O. (triglycerides of medium-chain fatty acids, a product of Nissh;n Seiyu Co.) and enclosing the resulting suspension in a soft gelatin shell. ~
, 1 1774~
Example 4 .
The duration of anti-inflammatory activity was tested as follows: Employing ED50 values determined in Example 3, the duration of anti-inflammatory activity was examined by varying the premedication time. The premedication time was defined as the time interval between the administration of a test compound and the injection of carrageenin. Tests were carried out in substantially the same manner as described in Example 3. The results thus obtained are shown in Table 3.
Tab'le 3 .. . , . ... _ _ . _ . . .
Rate of Suppresion of Edem`a (%) in Rats Premedi~ ,ation at Vario us Times _ 1 hr. 3 hrs. 6 hrs. 12'hrs, 24 hrs. 48 hrs .
. __ . ~ ., . __ . . .
Compound No. 1-1 55.7 54.9 48.3 40.322.6 9.8 Compound No. 1 2 56.6 54.8 43.2 39.120.7 3.4 .,,,_ ... . .. . _ . . ,. .
Piroxicam 57.6 55.3 40.0 38.815.3 1.7 Sudoxicam 49.8 52.1 39.5 31.610.4 -2.4 Isoxicam 54.2 54.2 45.8 36.319.5 1.1 Indomethacin 49.4 57.6 29.4 18.8-3.5 Diclofenac 45.9 24.7 17.6 11.8-1.2 Ex-amp'l-e' 5 The incidence of gastric disorders in rats was 'tested as follows:~ Eight~weeks-old male rats of the Wistar strain were used in groups of 5 to 7. After they were fasted ~ . - , " , .. . .
", .''','' " ." ' .
1 ~774~
for 18 hours or more, a test compound was administered orally.
Six hours later, each rat was sacrificed by decapitation.
The stomach was removed, filled with 10 ml of physiological saline, and then fixed in 5% formalin. After about 10 minutes, the stomach was incised through the greater curvature and the presence or absence of gastric disorders (in particular, erosion) was examined by visual observation. According to Litchfield~Wilcoxon's method, the dose causing erosion to occur in 50~ of the test animals, UD50, was calculated on an all-or-none basis. The results thus obtained are shown in Table 4.
Table 4 . . . .
. . . . . . .. , _ . . _ ., _ .
.Test Compound UDso (mg/kg, P ) Compound No. 1~1 200 Compound No. 1^2 297 .... _ .. _ .. - ... .
Piroxicam 8.2 Sudoxicam 11.8 Isoxicam 250 Indomethacin 5.4 Diclofenac 9.2 6~ethyl-2-pyridyl 5.1 ~ compound _ .
Example 6 Acute toxicity was tested as follows: Male mice of the ddY strain were used in groups of 5. A test compound was 4 8 ~1 suspended in a 0.2% carboxymethyl cellulose solution and orally administered in a dose of 0.1 ml/lOg of body weight. Thereafter, the animals were observed for 7 days. The LD50 value was calculated on the ~asis of the death rates on the final day.
The results thus obtained are shown in Table 5.
Table 5 .
.... _ . . . .. ... _ . . . ........ . . .. , ., . .. ~
Dose Number of Deaths/ LD
Test Compound (mg/kg, p.o.) Total Numb r of (mg/kg, p.o.) Compound No. 1~1 1,000 0/5 4,000 3,000 2/5 5,000 3/5 Compound No. 1-2 3,000 0/5 4,000 0/5>5,000 5,000 0/5 . . _. .... .. ....
Piroxicam ~100 0/5490 Sudoxicam 200 0/5500 1,000 5/5 Isoxicam 3,000 0/55,000 4,000 1/5 ' 5~000 3/5 __ .
.. . .
~~xa'mp-l'e' 7 .. . ..
Tablets containing Compound No. 1-1 were prepared according to the following recipe:
. . .
~ 177~8~ -Compound No. 1-1 10 mg Corn starch 270 mg Polyvinyl pyrrolidone15 mg Magnesium stearate 5 mg Using a tablet machine, the above ingredients were blended and compressed into a tablet.
E-xamp'l'e` 8 Capsules containing Compound No. l-l were prepared according to the ~ollowing recipe:
Compound No. l-l 10 mg Corn starch 230 mg Lactose 50 mg ~agnesium stearate 10 mg The`above ingredients were blended and enclosed in a hard gelatin shell.
E`~am'ple 9 Suppositories containing Compound No. l-l were prepared by suspending 20 mg of finely powdered Compound No. l-l in 5 ml of O.D.O. (triglycerides of medium-chain fatty acids, a product of Nissh;n Seiyu Co.) and enclosing the resulting suspension in a soft gelatin shell. ~
Claims (6)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of N-(6-halogeno-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide which comprises reacting a 3,4-dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate 1,1-dioxide with a 2-amino-6-halogenopyridine.
2. A process of claim 1, wherein 2-amino-6-chloropyridine is reacted with 3,4-dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate 1,1-dioxide.
3. A process of claim 1, wherein 2-amino-6-fluoropyridine is reacted with 3,4-dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate 1,1-dioxide.
4. A compound selected from the group consisting of N-(6-halogeno-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, when prepared by the process of claim 1.
5. The compound of claim 4 which is N-(6-chloro-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, when prepared by the process of claim 2.
6. The compound of claim 4 which is N-(6-fluoro-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, when prepared by the process of claim 3.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP86455/1980 | 1980-06-27 | ||
| JP8645580A JPS5714589A (en) | 1980-06-27 | 1980-06-27 | Benzothiazine derivative, its preparation and drug composition |
| JP56025002A JPS57140785A (en) | 1981-02-24 | 1981-02-24 | Benzothiazine derivative, its preparation, and pharmaceutical composition containing the same |
| JP25002/81 | 1981-02-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1177484A true CA1177484A (en) | 1984-11-06 |
Family
ID=26362607
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000380804A Expired CA1177484A (en) | 1980-06-27 | 1981-06-29 | Benzothiazine derivatives |
Country Status (6)
| Country | Link |
|---|---|
| CA (1) | CA1177484A (en) |
| DE (1) | DE3125216C2 (en) |
| FR (1) | FR2485532A1 (en) |
| GB (1) | GB2078738B (en) |
| IT (1) | IT1211068B (en) |
| NL (1) | NL186862C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR890001236B1 (en) * | 1985-10-02 | 1989-04-28 | 화이자 인코포레이티드 | Process for preparing antiinflammatory compositions |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3591584A (en) * | 1968-08-27 | 1971-07-06 | Pfizer | Benzothiazine dioxides |
| GB1308533A (en) * | 1969-06-02 | 1973-02-21 | Pfizer | Benzothiazine dioxides as anti-thombotic agents |
-
1981
- 1981-06-17 GB GB8118696A patent/GB2078738B/en not_active Expired
- 1981-06-24 IT IT8122548A patent/IT1211068B/en active
- 1981-06-24 NL NLAANVRAGE8103042,A patent/NL186862C/en not_active IP Right Cessation
- 1981-06-26 DE DE3125216A patent/DE3125216C2/en not_active Expired
- 1981-06-26 FR FR8112646A patent/FR2485532A1/en active Granted
- 1981-06-29 CA CA000380804A patent/CA1177484A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IT1211068B (en) | 1989-09-29 |
| FR2485532A1 (en) | 1981-12-31 |
| GB2078738A (en) | 1982-01-13 |
| NL186862B (en) | 1990-10-16 |
| DE3125216C2 (en) | 1984-08-16 |
| GB2078738B (en) | 1983-11-30 |
| IT8122548A0 (en) | 1981-06-24 |
| NL186862C (en) | 1991-03-18 |
| DE3125216A1 (en) | 1982-03-25 |
| NL8103042A (en) | 1982-01-18 |
| FR2485532B1 (en) | 1984-02-03 |
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