US3767653A - Thiazines - Google Patents

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US3767653A
US3767653A US00157678A US3767653DA US3767653A US 3767653 A US3767653 A US 3767653A US 00157678 A US00157678 A US 00157678A US 3767653D A US3767653D A US 3767653DA US 3767653 A US3767653 A US 3767653A
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alkyl
nitro
lower alkyl
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J Krapcho
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ER Squibb and Sons LLC
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    • 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
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/38—[b, e]-condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

  • X may be hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, haloalkylthio, alkoxy, hydroxy, alkylthio, nitro, alkylsulfonyl, amino, alkanoylamino or monoor dialkylamino wherein any of the foregoing alkyl or substituted alkyl radicals contain up to 8 carbon atoms; m may be 0, l, 2, 3 or 4; each A may be carbon, but one A may be nitrogen in any position provided 11 is 1; Y may be sulfur, sulfoxide, sulfonyl, or oxygen; 12 may be 0 to 1; R may be a straight or branched alkyl of up to 8 carbon atoms cycloalkyl of from 3 to 8 carbon atoms, phenyl X- substituted phenyl, pyridyl, thienyl, furyl, naphthy
  • 0 0 iiR alk may be a straight or branched carbon chain of up to 6 carbon atoms; and B may be a basic nitrogen-containing radical; and pharmaceutically acceptable acid-addition salts thereof; N oxides and pharmaceutically acceptable acid-addition salts thereof, and quaternary ammonium salts thereof.
  • alkylphenyl or alkenylphenyl wherein the alkyl or alkenyl radical may contain up to 4 carbon atoms either straight chain or branched;
  • Z may be OH 0:0, o
  • R is hydrogen, vinyl, allyl or R, or
  • R alk may be a straight or branched carbon chain of up to 6 carbon atoms; and B may be a basic nitrogen-containing radical; and pharmaceutically acceptable acid-addition salts thereof; N-oxides and pharmaceutically acceptable acid-addition salts thereof, and quaternary ammonium salts thereof.
  • the compounds of the present invention may be prepared according to the following reaction sequence wherein X, m, A, Y, n, alk, B, and R are as defined previously:
  • condensing agent there may be employed such materials as, e.g., NaH, NaOCH butyl Li, or K-t-butoxide.
  • the acylating agent may be an acyl halide
  • o Bil-hal or an ester of the formula 'wherein R is as defined previously, hal is halogen and R" is an organic radical, preferably a lower alkyl radical, e.g., methyl.
  • the acylation of the compound of Formula I to form the corresponding compound of Formula IIa takes place in a polar solvent such as, e.g., dimethylsulfoxide, tetrahydrofuran or ethyl acetate in the presence of a condensing agent.
  • a polar solvent such as, e.g., dimethylsulfoxide, tetrahydrofuran or ethyl acetate
  • the reaction is exothermic and cooling may be necessary to keep the reaction below about 30.
  • the mixture is heated to mod erately elevated temperature of from about 50 to about 75 for from about 0.5 hour to about 4 hours, preferably from about 1.5 hours to about 2.5 hours.
  • the pH of the resulting solution is then adjusted to from about 8.5 to about 9.5 to yield the compound of Formula Ha as a precipitate which is then purified by solvent and aqueous extraction and crystallization.
  • Compounds of Formula 1121 may be converted to the corresponding secondary alcohol (IIb) by treatment with a reducing agent such as, for example, NaBH or LiAlH Na isopropoxide or catalytically using, e.g., Pd on carbon, while the corresponding tertiary alcohol (He) may be obtained by reaction of the compound of Formula Hat with a Grignard reagent, RMghal, wherein R and hal are as previously defined.
  • a reducing agent such as, for example, NaBH or LiAlH Na isopropoxide or catalytically using, e.g., Pd on carbon
  • He tertiary alcohol
  • the hydroxyl group of the compounds of Formula Ilb and He may be esterified, for example, by use of an acid anhydride or an acyl halide of alkanoic acids of the formula 0 O 120 or RC% OH hal wherein R and hal are as previously defined.
  • the compounds of Formula 11 may be prepared by reacting an o-aminobenzenethiol or an X -substituted o-arninobenzenethiol of Formula ill with a halo-acetic acid, and reacting the resulting thiazinone of Formula IV with a haloalkylene-B compound to yield a compound of Formula 1-1.
  • the latter compound is then treated with a condensing agent and with an acylating agent to yield the corresponding compound of Formula IIa-l.
  • the compound of Formula Ila-1 may be converted to the corresponding compound of Formula IE) or Hc as described above.
  • R-imylating 0 ⁇ N/ agent ⁇ N/ elk-B zLlloB
  • suitable o-arninobenzenethiols which may be used as starting material in the foregoing reaction sequence are the following:
  • 2-aminobenzenethio1 4-fluoro-Z-aminobenzenethiol; S-fluoro-Z-aminobenzenethiol;
  • the compounds of Formula II may be prepared by reacting an o-nitrophenol or an X -substituted o-nitrophenol of Formula V with a haloacetic acid followed by reduction of the nitro group to an amino group. Cyclization takes place spontaneously following reduction to yield a compound of Formula VI. Reaction of the oxazinone compound of Formula VI with a haloalkylene-B compound yields a compound of Formula 1-2. The latter compound is then treated with a condensing agent and with an acylating agent to yield the corresponding compound of Formula Ila-2. The compound of Formula IIa-2 may be converted to the corresponding compound of Formula IIb or IIc as described previously.
  • the compounds of Formula II may be prepared by reacting an X -substituted dihydroindolone of Formula VII with a haloalkylene-B compound to yield a compound of Formula L3. The latter compound is then treated with a condensing agent and with an acylating agent to yield the corresponding compound of Formula Ila-3 which in turn may be converted to the corresponding compound of Formula IIb or as described previously.
  • the dihydroindolone may be prepared by reacting aniline or an X -substituted aniline with a-chloroacetic acid, and treating the resulting amide with AlCl (Friedel-Crafts reaction) to eifect ring closure.
  • suitable sub stituted anilines which may be used as starting materials in the foregoing reaction sequence are the following:
  • Z-methylaniline (o-toluidine), 3-methylani1ine (m-toluidine), 4-methylaniline (p-toluidine), 2,3-dimethylaniline, 2,4-dimethylaniline, 2,5-dimethylaniline, 3,4-dimethylaniline, 3,5-dimethylaniline, Z-ethylaniline, 2-isopropylaniline, 4-n-butylaniline,
  • Type of 1-4 compound of Formula I 1 l-pyrido[2,3-b][1,4]-thiazin-2(3 Ij )-one.
  • I-8 2g-pyrido[2,3-b] [1,41-oxazin-3 (4E) -one.
  • 1-9 2I :I-pyrido ⁇ 3,4-b] [1,41-oxazin-3 (4I I) -one.
  • 1-1 0 2g-pyrido[4,3-b] [1,4]-oxazin-3 (43) -one.
  • the pyridyl compounds of Formula 1-8, 1-9, 1-10 and 1-11 may be prepared in an analagous manner to the benzoxazines of Formula 1-2 by starting from a hydroxy nitropyridine or an X -substituted hydroxynitropyridine in place of an o-nitrophenol.
  • the sulfoxide or sulfonyl compounds of Formula II may be prepared by oxidizing the bivalent sulfur to the corresponding sulfoxide or sulfonyl.
  • the techniques for such oxidations involve the use of H 0 and KMnOl respectively, and are well known in the art.
  • the sulfoxide of a compound of Formula Ha may be obtained by treating a compound of Formula Ha for from about 2 to about 24 hours at room temperature with one equivalent of m-chloroperbenzoic acid; the sulfone of a compound of Formula He may be obtained by treating one of the bivalent sulfur compounds with two equivalents of m-chloroperbenzoic acid for the same time at room temperature, or for a shorter time with slight heating.
  • alkyl radical alk may be a straight or branched carbon chain of up to 6 carbon atoms.
  • radicals are the following: methyl, ethyl, n-propyl, ipropyl, n-butyl, i-butyl, t-butyl, n-pentyl, Z-methyl-n-butyl, neopentyl, n-hexyl, Z-methyI-n-pentyl, 3-methyl-n-pentyl, 2,2-dimethyl-n-butyl, and 2,3-dimethyl-n-butyl.
  • radicals represented by the basic nitrogen containing radical B are the following:
  • di(lower alkyl)amino e.g., N,N-dimethylamino
  • hydroxy lower alkyl (lower alkyl)amino (e.g., N-2- hydroxyethyl-N-methylamino di(hydroxy lower alkyl)amino;
  • N -dimethylaminoethylpiperazino (lower alkyl)-piperazino (e.g., N -rnethylpiperazino);
  • the lower alkyl and substituted lower alkyl radicals in the foregoing basic nitrogen containing radicals, B may contain up to 6 carbon atoms.
  • the compounds of the invention may be obtained as mixtures of diasteroisomeric compounds when they contain more than one asymmetric atom. Such mixtures of racemates can then be separated into individual racemic compounds.
  • salts those coming within the purview of this invention include the acid-addition salts, particularly the pharmaceutically acceptable acid-addition salts, N-oxides and pharmaceutically acceptable acid-addition salts of N-oxides, and pharmaceutically acceptable quaternary ammonium salts.
  • Acids useful for preparing these acidaddition salts include, inter alia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as maleic, fumaric, tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, salicylic, succinic acid, theophylline, 8-chlorotheophylline, p-aminobenzoic, p-acetamidobenzoic, nicotinic, methanesulfonic or cyclohexanesulfamic.
  • inorganic acids such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid
  • organic acids such as maleic, fumaric, tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, sal
  • the N-oxide may be formed by dissolving the free base of Formula II in a solvent inert to hydrogen peroxide, e.g., ethanol or chloroform, adding excess (on a molar basis) hydrogen peroxide, and allowing the mixture to stand at room temperature for several hours.
  • An acidaddition salt of the N-oxide may be formed by addition of the desired acid, for example, those mentioned above.
  • the quaternary ammonium salts include those formed with alkyl halides (e.g., methyl chloride, isobutyl bromide, dodecyl chloride and cetyl iodide), benzyl halides (e.g., benzyl chloride) and dilower alkyl sulfates (e.g., dimethyl sulfate).
  • alkyl halides e.g., methyl chloride, isobutyl bromide, dodecyl chloride and cetyl iodide
  • benzyl halides e.g., benzyl chloride
  • dilower alkyl sulfates e.g., dimethyl sulfate
  • the compounds of this invention are useful as antiinfiammatory agents and are efiective in the prevention and inhibition of granuloma tissuse formation in warm blooded animals, for example in a manner similar to phenylbutazone or indomethacin. They may be used to decrease joint swelling tenderness, pain and stifiness in mammalian species, e.g., in conditions such as rheumatoid arthritis.
  • the compounds of this invention or a physiologically acceptable acid-addition salt thereof may be compounded according to accepted pharmaceutical practice for admiinstration orally or by injection.
  • Suitable oral dosage forms are tablets, capsules, elixirs, suppositories, or powders, while solutions or suspensions are suitable for injection.
  • the quantity administered may be from about 25 mg. to about 2 gm. per day, and preferably from about 50 mg. to about 200 mg. per day.
  • EXAMPLE 1 (A) 4- [2- (dimethylamino ethyl] -2-1,4-benzothiazin- 3(4g)-one.A mixture of 108 g. of 1,4-benzothiazin- 3(4 I1)-one in 650 ml. of DMF is stirred and treated portionwise with 32.5 g. of sodium hydride (50% dispersion) while maintaining the temperature below 50. The solution is then heated to cooled to 25 and treated with 350 ml. of 2.8 N toluene solution of Z-dimethylaminoethyl chloride and 6 g. of sodium iodide.
  • This mixture is heated at 100-105 for 3 hours, cooled, poured into 2 liters of ice-water, and extracted with 500 ml. of ether (three times).
  • the organic phases are combined and extracted with a solution of 120 ml. of concentrated HCl in 500 ml. of water.
  • the aqueous phase is cooled and treated portionwise with 240 g. of -K CO
  • the liberated base is extracted with 500 ml. of ether (three times), the organic phases are combined, dried (Mgs filtered and the solvent evaporated.
  • the residue is fractionated to give 103.5 g. of colorless product; B.P. 146-149 (0.2 mm.).
  • the mixture is cooled intermittently to keep the temperature below 30.
  • the mixture is heated at 60-65 for 2 hours, kept overnight at room temperature, and poured with stirring into 600 ml. of ice-water.
  • the pH of the resulting solution is adjusted to 9.0 with 10% acetic acid to give a gummy precipitate.
  • the latter is extracted with chloroform (4X 200 ml.), dried (MgSO and the solvent evaporated.
  • the residue (ca. 50 g.) is taken up in 500 ml. of ether and extracted with a cold solution of 10 ml. of concentrated HCl in 120 ml. of water, followed by 50 ml. of water.
  • EXAMPLE 2 (A) 4-[3-(dimethylamino)propyl]2g 1,4 benzothiazin-3(4 Ii)-one.
  • the title product is prepared by react- 1 1 ing sixty grams (0.36 mole) of 1,4-benzothiazin-3(4 ]F I one in 360 ml. of DMF with 18 g. (0.37 mole) of 50% NaH, 260 ml. (0.55 mole) of a 2.1 N toluene solution of S-dimethylaminopropyl chloride, and 4 g. of sodium iodide according to the procedure described in Example 1, part (A); yield, 57.7 g.; B.P.. l57l60/0.2 mm.
  • Example 3.4 [3 dimethylamino)propyl]-2-pivaloyl- 2g-1,4-benzothiazin-3 (431) -one, hydrochloride 4 [3 (dimethylamino)propyl]-2g-l,4-benzothiazin- 3(4)-one (2.5 g.) prepared as described in Example 2, part (A) is reacted with 21 g. of methyl pivalate and 9 g. of 50% NaH in 100 ml. of DMSO as described in Example 1, part (B). There is only a slight temperature rise (31) and no vigorous foaming. The mixture is stirred at 70-75 for 3 hours, cooled, poured into 600 ml.
  • the vigorous reaction is accompanied by considerable foaming even with ice-cooling.
  • the syrupy base (12.2 g.) is taken up in 600 ml. of ether, cooled, and treated with 150 ml. of ether containing 4.5 ml. of 7.7 N alc. HCl to precipitate the hydrochloride as a yellow-orange amorphous solid. After cooling for 3 hours, the latter is collected under N washed with ether, and dried in vacuo; wt., 11 g.; M.P. 107-109 (foaming).
  • the free base from Example 1 (13.3 g.) is reacted with 4 g. of sodium borohydride in 160' ml. of methanol.
  • the viscous product (11.2 g.) is triturated with 40 ml. of boiling acetonitrile and cooled to give 5 g. of base; M.P. 151-153
  • the base (4.9 g.) is dissolved in a warm mixture of 15 ml. of chloroform and 15 ml. of methanol, cooled,
  • the free base from Example 2 (12.3 g.) is reacted with 3.6 g. of sodium borohydride in 150 ml. of methanol.
  • the crude syrupy base (12.1 g.) is crystallized from 130 ml. of isopropyl ether to give g. of solid; M.P. 105- 107 (s. 100).
  • CHaS O H H 2-(2-methylpiperidino)ethyl chloride.
  • N H CH3 H 2-(2, G-dimethylpiperidino) ethyl chloride.
  • 12..-. 5,7-dibromo-1II-pyrido-[4,3-b]- 3-benzoy1-1-[3,(dimethylamino)- [1,4]thiezin-2-(3H)-one.
  • a sample of the fumarate is treated with K CO to give the base as a brittle orange solid; M.P. 73-75 (s. 64).
  • Example 48 -2 benzoyl 4-[2-(dimethylamino)ethyl]- 2 I1-1,4-benzothiazin-3 (4g) -one-1-oxide, hydrochloride
  • Example 49 -2-benzoyl-4- [3 (dimethylamino)propyl]- ZE-lA-benzothiazin-El(4 E1)-one-1-oxide, hydrochloride
  • a chloroform solution containing 1 equivalent of m-chloroperbenzoic acid
  • Example 125 -3-benzoyl-l- ⁇ 2-(dimethylamino)ethyl] indolin-Z-one, hydrochloride Utilizing the procedure of Example 1 but substituting indolin-Z-one for 1,4-benzothiazin-3(4E)-one in part (A), the title product is prepared.
  • Example 126.3-benzoyll-[ 2- (dimethylamino) ethyl S-bromoindolin-Z-one, hydrochloride Following the procedure of Example 125 but substituting S-bromoindolin-Z-one for indolin-Z-one, the title prod- 5 net is obtained.
  • the title product is obtained.
  • Example 129 -2 furyl 4 [2-(piperidino)ethyl]-6- acetylamino 2E 1,4-benzothiazin-3 (4g)-one, hydrochloride
  • the title product is obtained.
  • Example 130.2 benzoyl-4-[2-(dimethylamino)ethyl]- 2g-1,4-benzothiazine-3 (4H) -one, methobromide
  • a solution of the free base of Example 1 in acetonitrile is treated with two equivalents of methyl bromide and the solution allowed to stand at room temperature for 8 hours. The solvent is removed to give the product.
  • Example 131.2 benzoyl-4-[2-(dimethylamino)ethyl]- 2 -1,4-benzothiazine-3 (4E) -one N-oxide
  • a solution of the free base of Example 1 in acetonitrile is treated with two equivalents of H 0 in acetic acid and the solution allowed to stand at room temperature for 8 hours. The solvent is removed to give the product.
  • a compound of the formula alk-B wherein X may be hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, haloalkylthio, alkoxy, hydroxy, alkylthio, nitro, alkylsulfonyl, amino, alkanoylamino, or monoor dialkylamino wherein any of the foregoing alkyl or substituted alkyl radicals contain up to 8 carbon atoms; m may be 0, 1, 2, 3 or 4; each A may be carbon, but one A may be nitrogen in any position; Y may be sulfur, sulfoxide, or sulfonyl; R may be a straight or branched alkyl of up to 8 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, phenyl, X-substituted phenyl, pyridyl, thienyl, furyl, naphthyl, alkylphenyl or al
  • alk may be a straight or branched carbon chain of up to 6 carbon atoms; and B may be a basic nitrogen-containing radical selected from the group consisting of amino, (lower alkyl)amino, di(lower alkyl)amino, (hydroxy lower alkyl) (lower alkyl)amino, di(hydroxy lower alkyl) amino, phenyl(lower alkyl)amino, N-phenyl lower alkyl- (lower alkyl)amino, piperidino, (lower alkyl)piperidino, di(lower alkyl) piperidino, (lower alkoxy)piperidino, homopiperidino, 2-, 3- or 4-pyridyl, 2-, 3- or 4-(N-lower alkyl piperidyl), pyrrolidino, (lower alkyl)pyrrolidino, di(lower alkyl)pyrrolidino, (lower alkoxy)pyrrolidino, 2-
  • a compound according to claim 1 having the formula A R 0-H wherein X, m, alk, B, Y, R and Z are as defined in claim 1.
  • a compound according to claim 1 having the name 2 benzoyl 4 [Z-(dimethylamino)ethyl]-2H-1,4-benzothiazin-3 (4;!) -one.
  • a compound according to claim 1 having the name 2 benzoyl 4 [3 (dimethylamino)propyl]-2H-1,4- benzothiazin-3 (4g) -one.
  • a compound according to claim 1 having the name 4 [3 (dimethylamino)propyl]-2-piva1oyl-2 Ii-1,4-benzothiazin-3 (4 I;I -one.
  • a compound according to claim 1 having the name 4 [3 (dimcthylamino)propyl]-2-isonicotinoyl-2g-1,4- benzothiazin3 (4g) -one.
  • a compound according to claim 1 having the name 3 benzoyl 1 [3-(dimethylamin0)propyl]JE-pyrido- [2,3-b ⁇ l,4]thiazin-2(3g)-one.
  • a compound according to claim 1 having the name 10 24 12.
  • a compound according to claim 1 having the name 4 [3 (dimethylamino)propy1]-2-(a-propylcinnamoyD- 2g- 1 4-benzothiazin-3 (411) -one.

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USB427946I5 (enrdf_load_stackoverflow) * 1973-12-26 1976-03-23
US4029508A (en) * 1974-08-14 1977-06-14 Fuji Photo Film Co., Ltd. Silver halide material containing a yellow color-forming coupler
US4033951A (en) * 1973-12-13 1977-07-05 Imperial Chemical Industries Limited Morpholine derivative of a 1,4-benzothiazin-3-one
US4079135A (en) * 1973-12-13 1978-03-14 Imperial Chemical Industries Limited Morpholine derivatives as antidepressants
FR2434160A1 (fr) * 1978-04-17 1980-03-21 Sumitomo Chemical Co Procede de production de nouveaux derives de la 1,4-benzothiazine et de leurs intermediaires, et herbicides contenant de tels composes
US4539329A (en) * 1982-05-11 1985-09-03 Imperial Chemical Industries, Plc 7'-Trifluoromethyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-triones as aldose reductase inhibitors
US4752609A (en) * 1985-06-20 1988-06-21 Pfizer Inc. Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds
WO1988005656A1 (en) * 1987-02-02 1988-08-11 Pfizer Inc. Anhydrous, crystalline sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide
US4784997A (en) * 1985-12-19 1988-11-15 Bayer Aktiengesellschaft 1-H-pyrido-[3,2-b][1,4]-thiazine
US4808601A (en) * 1984-09-19 1989-02-28 Pfizer Inc. Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds
EP0175551B1 (en) * 1984-09-19 1989-05-10 Pfizer Inc. Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds
EP0156603B1 (en) * 1984-03-19 1989-08-23 Pfizer Inc. 3-substituted 2-oxindole-1-carboxamides as analgesic and anti-inflammatory agents
EP0155828B1 (en) * 1984-03-19 1990-09-19 Pfizer Inc. Process for making 2-oxindole-1-carboxamides and intermediates therefor
EP2886541A1 (en) * 2013-12-19 2015-06-24 Sanofi Oxindole derivatives, preparation thereof and therapeutic use in the treatment of AMPK-related diseases
WO2017196970A1 (en) 2016-05-10 2017-11-16 Georgia State University Research Foundation, Inc. Heterocyclic derivatives for the thratment of rsv
US10906899B2 (en) 2016-05-10 2021-02-02 Georgia State University Research Foundation, Inc. Bicyclic fused pyrazole derivatives for the treatment of RSV

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE41420T1 (de) * 1984-02-07 1989-04-15 Pfizer 1,3-disubstituierte 2-oxindole und deren anwendung als analgetische und antiinflammatorische mittel.

Citations (1)

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US3471481A (en) * 1966-03-28 1969-10-07 Squibb & Sons Inc Benzothiazines

Patent Citations (1)

* Cited by examiner, † Cited by third party
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US3471481A (en) * 1966-03-28 1969-10-07 Squibb & Sons Inc Benzothiazines

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4033951A (en) * 1973-12-13 1977-07-05 Imperial Chemical Industries Limited Morpholine derivative of a 1,4-benzothiazin-3-one
US4079135A (en) * 1973-12-13 1978-03-14 Imperial Chemical Industries Limited Morpholine derivatives as antidepressants
USB427946I5 (enrdf_load_stackoverflow) * 1973-12-26 1976-03-23
US4006161A (en) * 1973-12-26 1977-02-01 Eli Lilly And Company Thio-substituted 2-oxo-indolines
US4029508A (en) * 1974-08-14 1977-06-14 Fuji Photo Film Co., Ltd. Silver halide material containing a yellow color-forming coupler
FR2434160A1 (fr) * 1978-04-17 1980-03-21 Sumitomo Chemical Co Procede de production de nouveaux derives de la 1,4-benzothiazine et de leurs intermediaires, et herbicides contenant de tels composes
US4539329A (en) * 1982-05-11 1985-09-03 Imperial Chemical Industries, Plc 7'-Trifluoromethyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-triones as aldose reductase inhibitors
EP0156603B1 (en) * 1984-03-19 1989-08-23 Pfizer Inc. 3-substituted 2-oxindole-1-carboxamides as analgesic and anti-inflammatory agents
EP0155828B1 (en) * 1984-03-19 1990-09-19 Pfizer Inc. Process for making 2-oxindole-1-carboxamides and intermediates therefor
US4808601A (en) * 1984-09-19 1989-02-28 Pfizer Inc. Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds
EP0175551B1 (en) * 1984-09-19 1989-05-10 Pfizer Inc. Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds
US4752609A (en) * 1985-06-20 1988-06-21 Pfizer Inc. Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds
US4784997A (en) * 1985-12-19 1988-11-15 Bayer Aktiengesellschaft 1-H-pyrido-[3,2-b][1,4]-thiazine
WO1988005656A1 (en) * 1987-02-02 1988-08-11 Pfizer Inc. Anhydrous, crystalline sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide
US5036099A (en) * 1987-02-02 1991-07-30 Pfizer Inc. Anhydrous, crystalline sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide
WO2015091937A1 (en) * 2013-12-19 2015-06-25 Sanofi Oxindole derivatives, preparation thereof and therapeutic use in the treatment of ampk-related diseases
EP2886541A1 (en) * 2013-12-19 2015-06-24 Sanofi Oxindole derivatives, preparation thereof and therapeutic use in the treatment of AMPK-related diseases
US10077237B2 (en) 2013-12-19 2018-09-18 Sanofi Oxindole derivatives, preparation thereof and therapeutic use in the treatment of AMPK-related diseases
AU2014368476B2 (en) * 2013-12-19 2018-10-04 Sanofi Oxindole derivatives, preparation thereof and therapeutic use in the treatment of AMPK-related diseases
CN106029656B (zh) * 2013-12-19 2019-07-26 赛诺菲 羟吲哚衍生物、其制备及其在治疗ampk相关疾病中的治疗用途
WO2017196970A1 (en) 2016-05-10 2017-11-16 Georgia State University Research Foundation, Inc. Heterocyclic derivatives for the thratment of rsv
EP3454896A4 (en) * 2016-05-10 2020-03-25 Georgia State University Research Foundation, Inc. HETEROCYCLIC DERIVATIVES FOR THE TREATMENT OF RSV
US10906899B2 (en) 2016-05-10 2021-02-02 Georgia State University Research Foundation, Inc. Bicyclic fused pyrazole derivatives for the treatment of RSV
US11084796B2 (en) 2016-05-10 2021-08-10 Georgia State University Research Foundation, Inc. Heterocyclic derivatives for the treatment of RSV

Also Published As

Publication number Publication date
DE2230592A1 (de) 1973-01-11
FR2147960B1 (enrdf_load_stackoverflow) 1976-03-05
CH546788A (fr) 1974-03-15
GB1388054A (en) 1975-03-19
FR2147960A1 (enrdf_load_stackoverflow) 1973-03-11

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