US3692780A - 4-substituted-2-alkyl-3-phenyl-2h-1,2-benzothiazine-1,1-dioxides and processes for their production - Google Patents
4-substituted-2-alkyl-3-phenyl-2h-1,2-benzothiazine-1,1-dioxides and processes for their production Download PDFInfo
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- US3692780A US3692780A US80788A US3692780DA US3692780A US 3692780 A US3692780 A US 3692780A US 80788 A US80788 A US 80788A US 3692780D A US3692780D A US 3692780DA US 3692780 A US3692780 A US 3692780A
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- phenyl
- alkyl
- benzothiazine
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- 238000000034 method Methods 0.000 title claims description 8
- 238000004519 manufacturing process Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- -1 4-palmitoxy-2-methyl-3-phenyl-2H-1,2-benzothiazine 1,1-Dioxide Chemical compound 0.000 claims description 10
- GHNLJDPNIAIWOQ-UHFFFAOYSA-N 2h-1$l^{6},2-benzothiazine 1,1-dioxide Chemical compound C1=CC=C2S(=O)(=O)NC=CC2=C1 GHNLJDPNIAIWOQ-UHFFFAOYSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 6
- 125000002252 acyl group Chemical group 0.000 abstract description 5
- 125000003710 aryl alkyl group Chemical group 0.000 abstract description 4
- 229940121363 anti-inflammatory agent Drugs 0.000 abstract description 3
- 239000002260 anti-inflammatory agent Substances 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000000538 analytical sample Substances 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 230000004968 inflammatory condition Effects 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000006324 decarbonylation Effects 0.000 description 1
- 238000006606 decarbonylation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- ARBOVOVUTSQWSS-UHFFFAOYSA-N hexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCC(Cl)=O ARBOVOVUTSQWSS-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/10—Spiro-condensed systems
Definitions
- ABSTRACT 4-substituted-2-alkyl-3-phenyl-2l-ll ,Z-benzothiazine- 1,1-dioxides having the following structural formula are disclosed wherein R is alkyl or aralkyl and R, is hydrogen or acyl. These compounds are useful as anti-inflammatory agents.
- R is alkyl or aralkyl and R is hydrogen or acyl.
- alkyl embraces both straight and branched alkyl radicals containing one to eight carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, n-amyl, and hexyl, 2-ethyl-2,3-dimethyl butyl and the like.
- aralkyl denotes groups such as benzyl.
- acyl embraces the radical derived from a carboxylic acid, preferably that of an alkanoic acid having one to 18 carbon atoms, such as formic, acetic, butyric, propionic and the like, benzoic acid or palmitic acid.
- the present invention also includes within its scope processes for the production of the above compounds as well as novel methods for treating inflammatory conditions.
- the compounds of this invention are useful as antiinflammatory agents, particularly those local inflammatory conditions such as dermatitis, urticara and the like.
- the compounds of this invention when applied locally at a dose range of from about 25 to 100 milligrams/per kg of body weight to an inflamed site of a mammalian host, such as rats, guinea pigs and the like, are found effective in suppressing the growth of granuloma tissue which has been induced by the implantation of a cotton pellet.
- the compounds of this invention are formulated into the usual dosage forms for topical application.
- a dermatologically acceptable vehicle such as petrolatum, vanishing cream base, talc and the like
- dosage forms such as ointments, creams and dusting powders.
- starting compound ll is treated with a peroxide, typically hydrogen peroxide at about ice water temperature, in the presence of a base in an inert solvent to obtain compound in.
- a peroxide typically hydrogen peroxide at about ice water temperature
- an acid typically boron trifluoride in an inert solvent such as methylene chloride
- R is hydrogen
- Subsequent treatment of those compounds of this invention where R is hydrogen with a base such as sodium hydride results in the fonnation of a salt which is in turn acylated with an acyl halide or an acid anhydride to give those compounds of the invention wherein R is acyl.
- the starting compound ll is known and is prepared in accordance with the procedure in J. Org. Chem. 30, 2241,0965).
- R is alkyl of one to eight carbon atoms or benzyl.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
4-substituted-2-alkyl-3-phenyl-2H-1,2-benzothiazine-1,1-dioxides having the following structural formula are disclosed
WHEREIN R1 is alkyl or aralkyl and R2 is hydrogen or acyl. These compounds are useful as anti-inflammatory agents.
WHEREIN R1 is alkyl or aralkyl and R2 is hydrogen or acyl. These compounds are useful as anti-inflammatory agents.
Description
United States Patent Zinnes et al.
[451 Sept. 19, 1972 [72] Inventors: Harold Zinnes, Rockaway; John Shave], Jr., Mendham, both of NJ.
[73] Assignee: Warner-Lambert Pharmaceutical Company, Morris Plains, NJ.
[22] Filed: Oct. 14, 1970 [21] Appl. No.: 80,788
[521 US. Cl ..260/243 R, 424/246, 260/240 F [51] Int. Cl. ..C07d 93/02 [58] Field of Search ..260/243 R [56] References Cited UNITED STATES PATENTS 3,591,584 7/1971 Lombardino ..260/243 3,459,748 8/ i969 Krapcho ..260/243 Primary Examiner-John M. Ford Attorney-Albert H. Graddis, Frank S. Chow, Neil D. Edwards, Edward G. Comrie and Anne M. Kelly [57] ABSTRACT 4-substituted-2-alkyl-3-phenyl-2l-ll ,Z-benzothiazine- 1,1-dioxides having the following structural formula are disclosed wherein R is alkyl or aralkyl and R, is hydrogen or acyl. These compounds are useful as anti-inflammatory agents.
7 Claims, No Drawings 4-SUBSTlTUTED-2-ALKYL-3-PHENYL-2H-l ,2- BENZOTHIAZINE-l l -DIOXIDES AND PROCESSES FOR THEIR PRODUCTION The present invention relates to 4-substituted-2- alkyl-3-phenyl-2H-l ,2-benzothiazine-l l -dioxides having the following structural formula:
wherein R is alkyl or aralkyl and R is hydrogen or acyl.
In the above definitions for R and R the term alkyl embraces both straight and branched alkyl radicals containing one to eight carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, n-amyl, and hexyl, 2-ethyl-2,3-dimethyl butyl and the like. The term aralkyl denotes groups such as benzyl. The term acyl" embraces the radical derived from a carboxylic acid, preferably that of an alkanoic acid having one to 18 carbon atoms, such as formic, acetic, butyric, propionic and the like, benzoic acid or palmitic acid.
The present invention also includes within its scope processes for the production of the above compounds as well as novel methods for treating inflammatory conditions.
The compounds of this invention are useful as antiinflammatory agents, particularly those local inflammatory conditions such as dermatitis, urticara and the like. For example, in a test conducted in accordance with the procedure set forth in Meier, et al, Experientia, Vol. 6, pp 469, 1950, the compounds of this invention when applied locally at a dose range of from about 25 to 100 milligrams/per kg of body weight to an inflamed site of a mammalian host, such as rats, guinea pigs and the like, are found effective in suppressing the growth of granuloma tissue which has been induced by the implantation of a cotton pellet.
In order to use the compounds of this invention, they are formulated into the usual dosage forms for topical application. For example, from about 0.l percent by weight to about percent by weight of the selected compound is blended with a dermatologically acceptable vehicle such as petrolatum, vanishing cream base, talc and the like and compounded into dosage forms such as ointments, creams and dusting powders. These dosage forms containing the selected compound or combinations thereof are applied liberally to an inflamed site two or three times daily.
According to the process of the invention, the above 4-substituted 1,2-benzothiazines are prepared in accordance with the reaction sequence set forth below.
Broadly speaking, starting compound ll is treated with a peroxide, typically hydrogen peroxide at about ice water temperature, in the presence of a base in an inert solvent to obtain compound in. Treatment of compound II] with an acid, typically boron trifluoride in an inert solvent such as methylene chloride gives a compound having formula IV. Refluxing compound IV with an aqueous acid results in decarbonylation yielding those compounds wherein R is hydrogen. Subsequent treatment of those compounds of this invention where R is hydrogen with a base such as sodium hydride results in the fonnation of a salt which is in turn acylated with an acyl halide or an acid anhydride to give those compounds of the invention wherein R is acyl.
The starting compound ll is known and is prepared in accordance with the procedure in J. Org. Chem. 30, 2241,0965).
intermediate compounds corresponding to Ill and W above are novel and they are also included within the scope of the present invention.
As it is obvious to those skilled in the art, by employing appropriately substituted starting materials, for example, where the aromatic rings are substituted by groups such as alkyl, aryl, alkoxy, amino, halogen, trifluoromethyl, nitro and the like, other 4-substitutedbenzothiazines can be readily obtained.
The following examples are given to further illustrate the invention.
EXAMPLE 1 3-Benzyl-3 ,a-epoxy-2-methyl-2l-l-l ,2-benzothiazin- 4( 3l-l)-one-l l -Dioxide To a solution of 18 g (0.06 mol) of 3-benzylidene-2- methyl-l ,2-benzothiazin-4( 3l-l)-one l ,l-dioxide in 300 ml of tetrahydrofuran was added ml of 30 percent aqueous hydrogen peroxide. To the stirred solution was slowly added 60 ml of 1.0 N sodium hydroxide, the temperature being maintained at 0 TO +5 during the addition. After stirring at this temperature for 30 minutes, the reaction mixture was poured into 3000 ml of ice-water and the resulting precipitate was collected and dissolved in dichloromethane. This solution was washed with water, dried over sodium sulfate, and evaporated to give a gummy residue. Trituration with petroleum ether (30-60) gave 15.5 g of white crystals, m.p. l20-123 dec which was of sufficient purity for use in the subsequent step. A portion was recrystallized from ethanol to give an analytical sample, m.p. l26-l28 dec. The material appeared to decompose on standing.
Anal. for CmHmNOqSZ EXAMPLE 2 EEQ 3-Formyl-2-methyl-3-phenyl-2H-l ,2-benzothiazin- 4(3H)-one-1,l-Dioxide A solution of 37.8 g (0.12 mol) of 3-benzyl3-,aepoxy-2-methyl-2H-1 ,2-benzothiazin-4(3H)-one-l ,1- dioxide in 1500 ml of dichloromethane was cooled to -5 and 300 ml of 46 percent boron trifluoride etherate was added. The resulting solution was allowed to stand at a temperature of 0 to 5 for 30 minutes and then poured into ice-water. The layers were separated and the organic layer was successively washed with water, in sodium hydroxide, and water. It was then dried over sodium sulfate and evaporated to a residue which was triturated with 50 ml of hot ether to give 23.5 g of crystals, m.p. 147148 (gas evol.). Recrystallization of a portion from a large volume of ether gave an analytical sample, m.p. 148-149 (gas evol.).
Anal. for C H NO S:
Calcd.: C 60.94H-4.16N -4.44S- 10.17
Found:C -6l.05 H -4.13 N-4.38 S- 10.32
EXAMPLE 3 NOHs \S/ 4-Hydroxy-2-methyl-3phenyl-2H-1,2-benzothiaiine 1,1-Dioxide A mixture of 15.7 g (0.05 mol) of 3-formyl-2-methyl- 3-phenyl-2H- l ,2-benzothiazin-4(3H)-one 1,1-dioxide, 200 ml of methanol, and 30 ml of 10 percent aqueous hydrochloric acid was refluxed for minutes. The solution was filtered while hit and concentrated to a volume of 75 ml. On standing at room temperature there was obtained 12.9 g of white crystals. The melting characteristics were dependent on the rate of heating. Samples immersed in the melting point bath at a rate of 1 per minute started to decompose at 132 and melted completely at 148. Samples kept at 132 for minutes melted completely. Recrystallization from methanol gave 1 1.0 g of product having the same melting characteristics.
Anal. for C, H, NO S:
Calcd.: C 67.70 H 4.56 N 4.87 S 11.16
Found: C- 62.84 H 4.58 N 4.91 S 11.22
EXAMPLE 4 /O\Ci(CHz)11CH3 NCH:
4 4-Palmitoxy-2-methyl-3-phenyl-2H-1 ,2-benzothiazine 1,1-Dioxide To a suspension of 0.03 mol of sodium hydride (55 percent mineral oil dispersion) in ml tetrahydrofuran, was added a solution of 8.61 g (0.03 mol) of 4-hydroxy-2-methyl-3-phenyl-2H-1 ,2- benzothiazine 1,1-dioxide in 50 ml of tetrahydrofuran, the temperature being maintained at 20. The mixture was stirred at this temperature for 2 hours and a solution of 8.25 g (0.03 mol) of palmitoyl chloride in 20 ml of tetrahydrofuran was added dropwise and stirring was continued at 20 for 2 hours. It was poured into 800 ml of cold 1 percent hydrochloric acid and extracted with dichloromethane. The organic layer was washed successively with cold 0.1 N sodium hydroxide and water, dried over sodium sulfate, and evaporated. The crystalline residue (17 g) was recrystallized from methanol-dichloromethane to give 9.5 g of product, m.p. 56.557.5.
Calcd.: C 70.82 H 8.24 N 2.66 S 6.10
Found: C 71.00 H 8.27 N 2.60 S 6.33
EXAMPLE 5 OCOCHa 4-Acetoxy-2-methyl-3phenyl-2H-1,2-benzothiazine 1,1-Dioxide To a suspension of 0.017 mol of sodium hydride (55 percent mineral oil dispersion) in 50 ml of tetrahydrofuran, was added a solution of 5.0 g (0.017 mol) of 4-hydroxy-2-methyl-3-phenyl-2H-l ,2- benzothiazine 1,1-dioxide in 50 ml of tetrahydrofuran, the temperature being maintained at 20. The mixture was stirred at this temperature for 2 hours and a solution of 1.36 g (0.017 mol) of acetyl chloride in 5 ml of tetrahydrofuran was added dropwise and stirring was continued at 20 for 2 hours. It was poured into 800 ml of cold 1 percent hydrochloric acid and extracted with dichloromethane. The organic layer was washed successively with cold 0.1 N sodium hydroxide and water, dried over sodium sulfate and evaporated. The residue was recrystallized from dichloromethane to give 4.5 g of product, m.p. 174-l 7 5.
Anal. for C H NO S:
Calcd.: C 61.99 H 4.59 N 4.25 S 9.73
Found: C 62.26 H 4.62 N 4.54 S 9.85
We claim:
1. A compound of the formula:
methanola. treating a compound of the formula: v
with a peroxide to give an epoxide of the formula:
b. treating said epoxide with an acid in an inert solvent to give a compound of the formula:
NR1 s ,9 f9.
and
c. refluxing said compound IV with an aqueous acid. 6. A compound of the formula:
wherein R, is alkyl of one to eight carbon atoms or benzyl.
' 7. A compound of the formula:
A CHO NR1 o o wherein nfis'lfifiBi he to eight carbon atoms or benzyl.
Claims (6)
- 2. A compound according to claim 1 which is 4-hydroxy-2-methyl-3-phenyl-2H,1,2-benzothiazine 1,1-Dioxide.
- 3. A compound according to claim 1 which is 4-palmitoxy-2-methyl-3-phenyl-2H-1,2-benzothiazine 1,1-Dioxide.
- 4. A compound according to claim 1 which is 4-acetoxy-2-methyl-3-phenyl-2H-1,2-benzothiazine 1,1-Dioxide.
- 5. A process for producing a compound according to claim 1 wherein R2 is hydrogen which comprises a. treating a compound of the formula:
- 6. A compound of the formula:
- 7. A compound of the formula:
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8078870A | 1970-10-14 | 1970-10-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3692780A true US3692780A (en) | 1972-09-19 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US80788A Expired - Lifetime US3692780A (en) | 1970-10-14 | 1970-10-14 | 4-substituted-2-alkyl-3-phenyl-2h-1,2-benzothiazine-1,1-dioxides and processes for their production |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3692780A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101362736B (en) * | 2008-09-08 | 2010-07-07 | 山东大学 | Benzosulfonamide CA-4 Analogs, Synthesis Method and Application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3459748A (en) * | 1967-04-28 | 1969-08-05 | Squibb & Sons Inc | Hydroxyalkylene-substituted benzoxazines and benzothiazines |
| US3591584A (en) * | 1968-08-27 | 1971-07-06 | Pfizer | Benzothiazine dioxides |
-
1970
- 1970-10-14 US US80788A patent/US3692780A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3459748A (en) * | 1967-04-28 | 1969-08-05 | Squibb & Sons Inc | Hydroxyalkylene-substituted benzoxazines and benzothiazines |
| US3591584A (en) * | 1968-08-27 | 1971-07-06 | Pfizer | Benzothiazine dioxides |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101362736B (en) * | 2008-09-08 | 2010-07-07 | 山东大学 | Benzosulfonamide CA-4 Analogs, Synthesis Method and Application |
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